Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 1654

Search results for: molecular docking

1654 Molecular Docking Assessment of Pesticides Binding to Bacterial Chitinases

Authors: Diana Larisa Vladoiu, Vasile Ostafe, Adriana Isvoran


Molecular docking calculations reveal that pesticides provide favorable interactions with the bacterial chitinases. Pesticides interact with both hydrophilic and aromatic residues involved in the active site of the enzymes, their positions partially overlapping the substrate and the inhibitors locations. Molecular docking outcomes, in correlation with experimental literature data, suggest that the pesticides may be degraded or having an inhibitor effect on the activity of these enzymes, depending of the application dose and rate.

Keywords: chitinases, inhibition, molecular docking, pesticides

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1653 Microbiological Activity and Molecular Docking Study of Selected Steroid Derivatives of Biomedical Importance

Authors: Milica Karadzic, Lidija Jevric, Sanja Podunavac-Kuzmanovic, Strahinja Kovacevic, Sinisa Markov, Aleksandar Okljesa, Andrea Nikolic, Marija Sakac, Katarina Penov Gasi


This study considered the microbiological activity determination and molecular docking study for selected steroid derivatives of biomedical importance. Minimal inhibitory concentration (MIC) was determined for steroid derivatives against Staphylococcus aureus using macrodilution method. Some of the investigated steroid derivatives express bacteriostatic effect against Staphylococcus aureus. Molecular docking approaches are the most widely used techniques for predicting the binding mode of a ligand. Molecular docking study was done for steroid derivatives for androgen receptor negative prostate cancer cell line (PC-3) toward Human Cytochrome P450 CYP17A1. The molecules that had the smallest experimental IC50 values confirmed their ability to dock into active place using suitable molecular docking procedure. The binding disposition of those molecules was thoroughly investigated. Microbiological analysis and molecular docking study were conducted with aim to additionally characterize selected steroid derivatives for future investigation regarding their biological activity and to estimate the binding-affinities of investigated derivatives. This article is based upon work from COST Action (TD1305), supported by COST (European Cooperation and Science and Technology).

Keywords: binding affinity, minimal inhibitory concentration, molecular docking, pc-3 cell line, staphylococcus aureus, steroids

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1652 Synthesis and Molecular Docking of Isonicotinohydrazide Derivatives as Anti-Tuberculosis Candidates

Authors: Ruswanto Ruswanto, Richa Mardianingrum, Tita Nofianti, Nur Rahayuningsih


Tuberculosis (TB) is a chronic disease as a result of Mycobacterium tuberculosis. It can affect all age groups, and hence, is a global health problem that causes the death of millions of people every year. One of the drugs used in tuberculosis treatment is isonicotinohydrazide. In this study, N'-benzoylisonicotinohydrazide derivative compounds (a-l) were prepared using acylation reactions between isonicotinohydrazide and benzoyl chloride derivatives, through the reflux method. Molecular docking studies suggested that all of the compounds had better interaction with Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) than isonicotinohydrazide. It can be concluded that N'-benzoylisonicotinohydrazide derivatives (a-l) could be used as anti-tuberculosis candidates. From the docking results revealed that all of the compounds interact well with InhA, with compound g (N'-(3-nitrobenzoyl)isonicotinohydrazide) exhibiting the best interaction.

Keywords: anti-tuberculosis , docking, InhA, N'-benzoylisonicotinohydrazide, synthesis

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1651 Molecular Docking and Synthesis of Nitrogen-Containing Bisphosphonates

Authors: S. Ghalem, M. Mesmoudi, I. Daoudand, H. Allali


The nitrogen-containing bisphosphonates (N-BPs) are well established as the treatments of choice for disorders of excessive bone resorption, myeloma and bone metastases, and osteoporosis. They inhibit farnesyl pyrophosphate synthase (FFPS), a key enzyme in the mevalonate pathway, resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton, adhesion/spreading, and invasion of cancer cells. A very few examples for synthesis of α-amino bisphosphonates based on several amino acids are known from the literature. In the present work, esters of aminoacid react with ketophsophonate (or their analog acid or acyl) to afford the desired products, α-iminophosphonates. The reaction of imine with dimethyl phosphate in the presence of catalytic amount of I2 give ester of α-aminobisphosphonate as sole product in good yield. Finally, we used computational docking methods to predict how several α-aminobisphosphonates bind to FPPS and how R and X influence. Pamidronate, β-aminobisphosphonate already marketed, was used as reference. These results are of interest since they represent a new and simple way to sythesize α-aminobisphosphonates with a free COOH group increased by R2 functionalisable and opening up the possibility of using the molecular docking to facilitate the design of other, novel FFPS inhibitors.

Keywords: drug research, cancer, α-amino bisphosphonates, molecular docking

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1650 Structure-Based Virtual Screening to Identify CLDN4 Inhibitors

Authors: Jayanthi Sivaraman


Claudins are the important components of the tight junctions that play a key role in paracellular permeability. Among various members of Claudin family, Claudin 4 (CLDN4) is found to be overexpressed in ovarian, pancreatic carcinomas and other epithelial malignancies. Therefore, in this study, an attempt has been made to identify potent inhibitors for CLDN4 from the ZINC database using virtual screening, molecular docking and molecular dynamics simulations. A well refined molecular model of CLDN4 was built using Prime of Schrodinger v10.2(Template- PDB ID: 4P79). Approximately, 6 million compounds from ZINC database are subjected to high-throughput virtual screening (HTVS) against the active site of CLDN4. Molecular docking using GLIDE predicted ARG31, ASN142, ASP146 and ARG158 as critically important residues. Furthermore, three compounds from ZINC database (ZINC96331839, ZINC36533519 and ZINC75819394) showed highly promising ADME properties and binding affinity with stable conformation. The therapeutic efficiency of these lead compounds is evaluated and confirmed by in-vitro and in-vivo studies which leads to the development of novel anti-cancer drugs.

Keywords: ADME property, inhibitors, molecular docking, virtual screening

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1649 QSAR, Docking and E-pharmacophore Approach on Novel Series of HDAC Inhibitors with Thiophene Linker as Anticancer Agents

Authors: Harish Rajak, Preeti Patel


HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. The 3D-QSAR and Pharmacophore modeling studies were performed to identify important pharmacophoric features and correlate 3D-chemical structure with biological activity. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with well-assigned HDAC inhibitory activity was used for 3D-QSAR model development. Best 3D-QSAR model, which is a five PLS factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811) and standard deviation (0.0952). Molecular docking were performed using Histone Deacetylase protein (PDB ID: 1t69) and prepared series of hydroxamic acid based HDAC inhibitors. Docking study of compound 43 show significant binding interactions Ser 276 and oxygen atom of dioxine cap region, Gly 151 and amino group and Asp 267 with carboxyl group of CONHOH, which are essential for anticancer activity. On docking, most of the compounds exhibited better glide score values between -8 to -10.5. We have established structure activity correlation using docking, energetic based pharmacophore modelling, pharmacophore and atom based 3D QSAR model. The results of these studies were further used for the design and testing of new HDAC analogs.

Keywords: Docking, e-pharmacophore, HDACIs, QSAR, Suberoylanilidehydroxamic acid.

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1648 Docking and Dynamic Molecular Study of Isoniazid Derivatives as Anti-Tuberculosis Drug Candidate

Authors: Richa Mardianingrum, Srie R. N. Endah


In this research, we have designed four isoniazid derivatives i.e., isonicotinohydrazide (1-isonicotinoyl semicarbazide, 1-thiosemi isonicotinoyl carbazide, N '-(1,3-dimethyl-1 h-pyrazole-5-carbonyl) isonicotino hydrazide, and N '-(1,2,3- 4-thiadiazole-carbonyl) isonicotinohydrazide. The docking and molecular dynamic have performed to them in order to study its interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA). Based on this research, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (INHA) receptor, so they could be used as an anti-tuberculosis drug candidate.

Keywords: anti-tuberculosis, docking, Inhibin alpha subunit, InhA, inhibition, synthesis, isonicotinohydrazide

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1647 Binding Studies of Complexes of Anticancer Drugs with DNA and Enzymes Involved in DNA Replication Using Molecular Docking and Cell Culture Techniques

Authors: Fouzia Perveen, Rumana Qureshi


The presently studied twelve anticancer drugs are the cytotoxic agents which inhibit the replication of DNA and activity of enzymes involved in DNA replication namely topoisomerase-II, polymerase and helicase and have shown remarkable anticancer activity in clinical trials. In this study, we performed molecular docking studies of twelve antitumor drugs against DNA and DNA enzymes in the presence and absence of ascorbic acid (AA) and developed the quantitative structure-activity relationship (QSAR) model for anticancer activity screening. A number of electronic and steric descriptors were calculated using MOE software package. QSAR was established showing a correlation of binding strength with various physicochemical descriptors. Out of these twelve, eight cytotoxic drugs were tested on Non-Small Cell Lung Cancer cell lines (H-157 and H-1299) in the absence and presence of ascorbic acid and experimental IC50 values were calculated. From the docking studies, binding constants were calculated indicating the strength of drug-DNA and drug-enzyme complex formation and it was correlated to the IC50 values (both experimental and theoretical). These results can offer useful references for directing the molecular design of DNA enzyme inhibitor with improved anticancer activity.

Keywords: ascorbic acid, binding constant, cytotoxic agents, cell culture, DNA, DNA enzymes, molecular docking

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1646 2-Thioimidazole Analogues: Synthesis, in silico Studies and in vitro Anticancer and Antiprotozoal Evaluation

Authors: Drashti G. Daraji, Rosa E. Moo-Puc, Hitesh D. Patel


Substituted 2-Thioimidazole analogues have been synthesized and confirmed by advanced spectroscopic techniques. Among them, ten compounds have been selected and evaluated for their in vitro anti-cancer activity at the National Cancer Institute (NCI) for testing against a panel of 60 different human tumor cell lines derived from nine neoplastic cancer types. Furthermore, synthesized compounds were tested for their in vitro antiprotozoal activity, and none of them exhibited significant potency against antiprotozoans. It was observed that the tested all compounds seem effective on the UACC-62 melanoma cancer cell line as compared to other cancer cell lines and also exhibited the least potent in the Non-Small Cell Lung Cancer cell line in one-dose screening. In silico studies of these derivatives were carried out by molecular docking techniques and Absorption, Distribution, Metabolism, and Excretion (ADME) using Schrödinger software to find potent B-Raf kinase inhibitor (PDB ID: 3OG7). All the compounds have been performed for docking study; Compound D4 has a good docking score for melanoma cancer as compared with other.

Keywords: anticancer activity, cancer cell line, 2-thio imidazole, one-dose assay, molecular docking

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1645 An Inverse Docking Approach for Identifying New Potential Anticancer Targets

Authors: Soujanya Pasumarthi


Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA-1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified in silico should be experimentally screened for their ability to inhibitcancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce theviability of BT-474 breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of mutant p53 to DNA in BT- 474cells (which highly express p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation.

Keywords: inverse docking, in silico screening, protein-ligand interactions, molecular docking

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1644 Synthesis, Inhibitory Activity, and Molecular Modelling of 2-Hydroxy-3-Oxo-3-Phenylpropionate Derivatives as HIV-1-Integrase Inhibitors

Authors: O. J. Jesumoroti, Faridoon, R. Klein, K. A. Iobb, D. Mnkadhla, H. C. Hoppe, P. T. Kaye


The 1, 3-aryl diketo acids (DKA) based agents represent an important class of HIV integrase (IN) strand transfer inhibitors. In other to study the chelating role of the divalent metal ion in the inhibition of IN strand transfer, we designed and synthesized a series of 2-hydroxy-3-oxo-3-phenyl propionate derivatives with the notion that such compounds could interact with the divalent ion in the active site of IN. The synthetic sequence to the desired compounds involves the concept of Doebner knoevenagel condensation, Fischer esterification and ketohydroxylation using neuclophilic re-oxidant; compounds were characterized by their IR, IHNMR, 13CNMR, HRMS spectroscopic data and melting point determination. Also, molecular docking was employed in this study and it was revealed that there is interaction with the active site of the enzyme. However, there is disparity in the corresponding anti-HIV activity determined by the experimental bioassay. These compounds lack potency at low micromolar concentration when compared to the results of the docking studies. Nevertheless, the results of the study suggest modification of the aryl ring with one or two hydroxyl groups to improve the inhibitory activity.

Keywords: anti-HIV-1 integrase, ketohydroxylation, molecular docking, propionate derivatives

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1643 In-Silico Investigation of Phytochemicals from Ocimum Sanctum as Plausible Antiviral Agent in COVID-19

Authors: Dileep Kumar, Janhavi Ramchandra Rao Kumar, Rao


COVID-19 has ravaged the globe, and it is spreading its Spectre day by day. In the absence of established drugs, this disease has created havoc. Some of the infected persons are symptomatic or asymptomatic. The respiratory system, cardiac system, digestive system, etc. in human beings are affected by this virus. In our present investigation, we have undertaken a study of the Indian Ayurvedic herb, Ocimum sanctum against SARS-CoV-2 using molecular docking and dynamics studies. The docking analysis was performed on the Glide module of Schrödinger suite on two different proteins from SARS-CoV-2 viz. NSP15 Endoribonuclease and spike receptor-binding domain. MM-GBSA based binding free energy calculations also suggest the most favorable binding affinities of carvacrol, β elemene, and β caryophyllene with binding energies of −61.61, 58.23, and −54.19 Kcal/mol respectively with spike receptor-binding domain and NSP15 Endoribonuclease. It rekindles our hope for the design and development of new drug candidates for the treatment of COVID19.

Keywords: molecular docking, COVID-19, ocimum sanctum, binding energy

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1642 Synthesis, Molecular Docking, and Cytotoxic Activity of Novel Triazolopyridazine Derivatives

Authors: Azza T. Tahera, Eman M. Ahmeda, Nadia A. Khalila, Yassin M. Nissanb


New 3-(pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine derivatives 2a-i, 4a,b and 6a,b were designed, synthesized and evaluated as cytotoxic agents. All compounds were investigated for their in vitro cytotoxicity at a single dose 10-5M concentration towards 60 cancer cell lines according to USA NCI protocol. The preliminary screening results showed that the majority of tested compounds exhibited remarkable activity against SR (leukemia) cell panel. Molecular docking for all synthesized compounds was performed on the active site of c-Met kinase. The most active compounds, 2f and 4a were further evaluated at a seven dose level screening and their IC50 as a c-Met kinase inhibitors were determined in vitro.

Keywords: triazolopyridazines, pyridazines, cytotoxic activity, cell panel

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1641 Docking, Pharmacophore Modeling and 3d QSAR Studies on Some Novel HDAC Inhibitors with Heterocyclic Linker

Authors: Harish Rajak, Preeti Patel


The application of histone deacetylase inhibitors is a well-known strategy in prevention of cancer which shows acceptable preclinical antitumor activity due to its ability of growth inhibition and apoptosis induction of cancer cell. Molecular docking were performed using Histone Deacetylase protein (PDB ID:1t69) and prepared series of hydroxamic acid based HDACIs. On the basis of docking study, it was predicted that compound 1 has significant binding interaction with HDAC protein and three hydrogen bond interactions takes place, which are essential for antitumor activity. On docking, most of the compounds exhibited better glide score values between -8 to -10 which is close to the glide score value of suberoylanilide hydroxamic acid. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. The 3D-QSAR models provided a good correlation between predicted and actual anticancer activity. Best QSAR model showed Q2 (0.7974), R2 (0.9200) and standard deviation (0.2308). QSAR visualization maps suggest that hydrogen bond acceptor groups at carbonyl group of cap region and hydrophobic groups at ortho, meta, para position of R9 were favorable for HDAC inhibitory activity. We established structure activity correlation using docking, pharmacophore modeling and atom based 3D QSAR model for hydroxamic acid based HDACIs.

Keywords: HDACIs, QSAR, e-pharmacophore, docking, suberoylanilide hydroxamic acid

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1640 Quantitative Structure Activity Relationship and Insilco Docking of Substituted 1,3,4-Oxadiazole Derivatives as Potential Glucosamine-6-Phosphate Synthase Inhibitors

Authors: Suman Bala, Sunil Kamboj, Vipin Saini


Quantitative Structure Activity Relationship (QSAR) analysis has been developed to relate antifungal activity of novel substituted 1,3,4-oxadiazole against Candida albicans and Aspergillus niger using computer assisted multiple regression analysis. The study has shown the better relationship between antifungal activities with respect to various descriptors established by multiple regression analysis. The analysis has shown statistically significant correlation with R2 values 0.932 and 0.782 against Candida albicans and Aspergillus niger respectively. These derivatives were further subjected to molecular docking studies to investigate the interactions between the target compounds and amino acid residues present in the active site of glucosamine-6-phosphate synthase. All the synthesized compounds have better docking score as compared to standard fluconazole. Our results could be used for the further design as well as development of optimal and potential antifungal agents.

Keywords: 1, 3, 4-oxadiazole, QSAR, multiple linear regression, docking, glucosamine-6-phosphate synthase

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1639 Synthesis, Molecular-Docking, and Biological Evaluation of Thiazolopyrimidine Carboxylates as Potential Antidiabetic and Antibacterial Agents

Authors: Iram Batool, Aamer Saeed, Irfan Zia Qureshi, Ayesha Razzaq, Saima Kalsoom


Heterocyclic compounds analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. A series of new thiazolopyrimidine carboxylates were conveniently synthesized by one-pot three-component reaction of ethyl acetoacetate, 2-aminothiazole and benzaldehyde substituted with electron-donating and electron-withdrawing groups in order to find some more potent antidiabetic and antibacterial drugs. The structures of synthesized compounds were characterized by elemental analysis, IR, 1H NMR, 13C NMR spectroscopy. An in vitro antidiabetic effect was evaluated in adult male BALB/c mice and antibacterial activities were tested against Micrococcus luteus, Salmonella typhimurium, Bacillus subtilis, Bordetella bronchiseptica and Escherichia coli. Some of the tested compounds proved to possess good to excellent activities more than the reference drugs. An in silico molecular docking was also performed on synthesized compounds. The current study is expected to provide useful insights into the design of antidiabetic and antibacterial drugs and understanding the mechanism by which such drugs interact with RNA and diabetes target and exert their biochemical action.

Keywords: antidiabetic, antibacterial, MOE docking, thiazolopyrimidine

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1638 Cholinesterase Inhibitory Indole Alkaloids from the Bark of Rauvolfia reflexa

Authors: Mehran Fadaeinasab, Alireza Basiri, Yalda Kia, Hamed Karimian, Hapipah Mohd Ali, Vikneswaran Murugaiyah


Two new, rauvolfine C and 3- methyl-10,11-dimethoxyl-6- methoxycarbonyl- β- carboline, along with five known indole alkaloids, macusine B, vinorine, undulifoline, isoresrpiline and rescinnamine were isolated from the bark of Rauvolfia reflexa. All the compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 πM, except rauvolfine C that was inactive against acetylcholinesterase (AChE). Rescinnamine, a dual inhibitor was found to be the most potent inhibitor among the isolated alkaloids against both AChE and butyrylcholinesterase (BChE). Molecular docking revealed that rescinnamine interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding.

Keywords: Rauvolfia reflexa, indole alkaloids, acetylcholinesterase, butyrylcholinesterase, molecular docking

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1637 Scheduling of Cross-Docking Center: An Auction-Based Algorithm

Authors: Eldho Paul, Brijesh Paul


This work proposes an auction mechanism based solution methodology for the optimum scheduling of trucks in a cross-docking centre. The cross-docking centre is an important element of lean supply chain. It reduces the amount of storage and transportation costs in the distribution system compared to an ordinary warehouse. Better scheduling of trucks in a cross-docking center is the best way to reduce storage and transportation costs. Auction mechanism is commonly used for allocation of limited resources in different real-life applications. Here, we try to schedule inbound trucks by integrating auction mechanism with the functioning of a cross-docking centre. A mathematical model is developed for the optimal scheduling of inbound trucks based on the auction methodology. The determination of exact solution for problems involving large number of trucks was found to be computationally difficult, and hence a genetic algorithm based heuristic methodology is proposed in this work. A comparative study of exact and heuristic solutions is done using five classes of data sets. It is observed from the study that the auction-based mechanism is capable of providing good solutions to scheduling problem in cross-docking centres.

Keywords: auction mechanism, cross-docking centre, genetic algorithm, scheduling of trucks

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1636 Computational Analysis of Potential Inhibitors Selected Based on Structural Similarity for the Src SH2 Domain

Authors: W. P. Hu, J. V. Kumar, Jeffrey J. P. Tsai


The inhibition of SH2 domain regulated protein-protein interactions is an attractive target for developing an effective chemotherapeutic approach in the treatment of disease. Molecular simulation is a useful tool for developing new drugs and for studying molecular recognition. In this study, we searched potential drug compounds for the inhibition of SH2 domain by performing structural similarity search in PubChem Compound Database. A total of 37 compounds were screened from the database, and then we used the LibDock docking program to evaluate the inhibition effect. The best three compounds (AP22408, CID 71463546 and CID 9917321) were chosen for MD simulations after the LibDock docking. Our results show that the compound CID 9917321 can produce a more stable protein-ligand complex compared to other two currently known inhibitors of Src SH2 domain. The compound CID 9917321 may be useful for the inhibition of SH2 domain based on these computational results. Subsequently experiments are needed to verify the effect of compound CID 9917321 on the SH2 domain in the future studies.

Keywords: nonpeptide inhibitor, Src SH2 domain, LibDock, molecular dynamics simulation

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1635 Molecular Basis for Amyloid Inhibition by L-Dopa: Implication towards Systemic Amyloidosis

Authors: Rizwan H. Khan, Saima Nusrat


Despite the fact that amyloid associated neurodegenerative diseases and non-neuropathic systemic amyloidosis have allured the research endeavors, as no curative drugs have been proclaimed up till now except for symptomatic cure. Therapeutic compounds which can diminish or disaggregate such toxic oligomers and fibrillar species have been examined and more are on its way. In the present study, we had reported an extensive biophysical, microscopic and computational study, revealing that L-3, 4-dihydroxyphenylalanine (L-Dopa) possess undeniable potency to inhibit heat induced human lysozyme (HL) amyloid fibrillation and also retain the fibril disaggregating potential. L-Dopa interferes in the amyloid fibrillogenesis process by interacting hydrophobically and also by forming hydrogen bonds with the amino acid residues found in amyloid fibril forming prone region of HL as elucidated by molecular docking results. L-Dopa also disaggregates the mature amyloid fibrils into some unorganised species. Thus, L-Dopa and related compounds can work as a promising inhibitor for the therapeutic advancement prospective against systemic amyloidosis.

Keywords: amyloids, disaggregation, human lysozyme, molecular docking

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1634 Molecular Design and Synthesis of Heterocycles Based Anticancer Agents

Authors: Amna J. Ghith, Khaled Abu Zid, Khairia Youssef, Nasser Saad


Backgrounds: The multikinase and vascular endothelial growth factor (VEGF) receptor inhibitors interrupt the pathway by which angiogenesis becomes established and promulgated, resulting in the inadequate nourishment of metastatic disease. VEGFR-2 has been the principal target of anti-angiogenic therapies. We disclose the new thieno pyrimidines as inhibitors of VEGFR-2 designed by a molecular modeling approach with increased synergistic activity and decreased side effects. Purpose: 2-substituted thieno pyrimidines are designed and synthesized with anticipated anticancer activity based on its in silico molecular docking study that supports the initial pharmacophoric hypothesis with a same binding mode of interaction at the ATP-binding site of VEGFR-2 (PDB 2QU5) with high docking score. Methods: A series of compounds were designed using discovery studio 4.1/CDOCKER with a rational that mimic the pharmacophoric features present in the reported active compounds that targeted VEGFR-2. An in silico ADMET study was also performed to validate the bioavailability of the newly designed compounds. Results: The Compounds to be synthesized showed interaction energy comparable to or within the range of the benzimidazole inhibitor ligand when docked with VEGFR-2. ADMET study showed comparable results most of the compounds showed absorption within (95-99) zone varying according to different substitutions attached to thieno pyrimidine ring system. Conclusions: A series of 2-subsituted thienopyrimidines are to be synthesized with anticipated anticancer activity and according to docking study structure requirement for the design of VEGFR-2 inhibitors which can act as powerful anticancer agents.

Keywords: docking, discovery studio 4.1/CDOCKER, heterocycles based anticancer agents, 2-subsituted thienopyrimidines

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1633 Molecular Insights into the 5α-Reductase Inhibitors: Quantitative Structure Activity Relationship, Pre-Absorption, Distribution, Metabolism, and Excretion and Docking Studies

Authors: Richa Dhingra, Monika, Manav Malhotra, Tilak Raj Bhardwaj, Neelima Dhingra


5-Alpha-reductases (5AR), a membrane bound, NADPH dependent enzyme and convert male hormone testosterone (T) into more potent androgen dihydrotestosterone (DHT). DHT is the required for the development and function of male sex organs, but its overproduction has been found to be associated with physiological conditions like Benign Prostatic Hyperplasia (BPH). Thus the inhibition of 5ARs could be a key target for the treatment of BPH. In present study, 2D and 3D Quantitative Structure Activity Relationship (QSAR) pharmacophore models have been generated for 5AR based on known inhibitory concentration (IC₅₀) values with extensive validations. The four featured 2D pharmacophore based PLS model correlated the topological interactions (–OH group connected with one single bond) (SsOHE-index); semi-empirical (Quadrupole2) and physicochemical descriptors (Mol. wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and has the highest correlation coefficient (r² = 0.98, q² =0.84; F = 57.87, pred r² = 0.88). Internal and external validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic field effects and steric interactions generated by 3D-QSAR showed interesting results in terms of internal and external predictability. The well validated 2D Partial Least Squares (PLS) and 3D k-nearest neighbour (kNN) models were used to search novel 5AR inhibitors with different chemical scaffold. To gain more insights into the molecular mechanism of action of these steroidal derivatives, molecular docking and in silico absorption, distribution, metabolism, and excretion (ADME) studies were also performed. Studies have revealed the hydrophobic and hydrogen bonding of the ligand with residues Alanine (ALA) 63A, Threonine (THR) 60A, and Arginine (ARG) 456A of 4AT0 protein at the hinge region. The results of QSAR, molecular docking, in silico ADME studies provide guideline and mechanistic scope for the identification of more potent 5-Alpha-reductase inhibitors (5ARI).

Keywords: 5α-reductase inhibitor, benign prostatic hyperplasia, ligands, molecular docking, QSAR

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1632 Searching for Novel Scaffolds of Triazole Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

Authors: Tomasz Frączek, Agata Paneth, Rafał Kamiński, Agnieszka Krakowiak, Piotr Paneth


Azoles are a promising class of the new generation of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. To find novel extensions for this primary scaffold, we explored the 5-position substitution of triazole NNRTIs using molecular docking followed by synthesis of selected compounds. We discovered that heterocyclic substituents in 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with 4-membered thioglycolamide linker. This substitution seems to be viable only for compounds with a shorter 2-membered linker such as in derivatives of 4‐benzyl‐3‐(benzyl-sulfanyl)‐5‐(thiophen‐2‐yl)‐4H‐1,2,4‐triazole reported earlier. A new scaffold of 2‐[(4‐benzyl‐5‐methyl‐4H‐1,2,4‐triazol‐3‐yl)sulfanyl]‐N‐phenylacetamide has been identified in this study.

Keywords: docking, molecular modeling, drug design, novel scaffolds

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1631 Investigating Anti-Tumourigenic and Anti-Angiogenic Effects of Resveratrol in Breast Carcinogenesis Using in-Silico Algorithms

Authors: Asma Zaib, Saeed Khan, Ayaz Ahmed Noonari, Sehrish Bint-e-Mohsin


Breast cancer is the most common cancer among females worldwide and is estimated that more than 450,000 deaths are reported each year. It accounts for about 14% of all female cancer deaths. Angiogenesis plays an essential role in Breast cancer development, invasion, and metastasis. Breast cancer predominantly begins in luminal epithelial cells lining the normal breast ducts. Breast carcinoma likely requires coordinated efforts of both increased proliferation and increased motility to progress to metastatic stages.Resveratrol: a natural stilbenoid, has anti-inflammatory and anticancer effects that inhibits proliferation of variety of human cancer cell lines, including breast, prostate, stomach, colon, pancreatic, and thyroid cancers.The objective of this study is:To investigate anti-neoangiogenesis effects of Resveratrol in breast cancer and to analyze inhibitory effects of resveratrol on aromatase, Erα, HER2/neu, and VEGFR.Docking is the computational determination of binding affinity between molecule (protein structure and ligand).We performed molecular docking using Swiss-Dock and to determine docking effects of (1) Resveratrol with Aromatase, (2) Resveratrol with ERα (3) Resveratrol with HER2/neu and (4) Resveratrol with VEGFR2.Docking results of resveratrol determined inhibitory effects on aromatase with binding energy of -7.28 kcal/mol which shows anticancerous effects on estrogen dependent breast tumors. Resveratrol also show inhibitory effects on ERα and HER2/new with binging energy -8.02, and -6.74 respectively; which revealed anti-cytoproliferative effects upon breast cancer. On the other hand resveratrol v/s VEGFR showed potential inhibitory effects on neo-angiogenesis with binding energy -7.68 kcal/mol, angiogenesis is the important phenomenon that promote tumor development and metastasis. Resveratrol is an anti-breast cancer agent conformed by in silico studies, it has been identified that resveratrol can inhibit breast cancer cells proliferation by acting as competitive inhibitor of aromatase, ERα and HER2 neo, while neo-angiogemesis is restricted by binding to VEGFR which authenticates the anti-carcinogenic effects of resveratrol against breast cancer.

Keywords: angiogenesis, anti-cytoproliferative, molecular docking, resveratrol

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1630 Biflavonoids from Selaginellaceae as Epidermal Growth Factor Receptor Inhibitors and Their Anticancer Properties

Authors: Adebisi Adunola Demehin, Wanlaya Thamnarak, Jaruwan Chatwichien, Chatchakorn Eurtivong, Kiattawee Choowongkomon, Somsak Ruchirawat, Nopporn Thasana


The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein involved in cellular signalling processes and, its aberrant activity is crucial in the development of many cancers such as lung cancer. Selaginellaceae are fern allies that have long been used in Chinese traditional medicine to treat various cancer types, especially lung cancer. Biflavonoids, the major secondary metabolites in Selaginellaceae, have numerous pharmacological activities, including anti-cancer and anti-inflammatory. For instance, amentoflavone induces a cytotoxic effect in the human NSCLC cell line via the inhibition of PARP-1. However, to the best of our knowledge, there are no studies on biflavonoids as EGFR inhibitors. Thus, this study aims to investigate the EGFR inhibitory activities of biflavonoids isolated from Selaginella siamensis and Selaginella bryopteris. Amentoflavone, tetrahydroamentoflavone, sciadopitysin, robustaflavone, robustaflavone-4-methylether, delicaflavone, and chrysocauloflavone were isolated from the ethyl-acetate extract of the whole plants. The structures were determined using NMR spectroscopy and mass spectrometry. In vitro study was conducted to evaluate their cytotoxicity against A549, HEPG2, and T47D human cancer cell lines using the MTT assay. In addition, a target-based assay was performed to investigate their EGFR inhibitory activity using the kinase inhibition assay. Finally, a molecular docking study was conducted to predict the binding modes of the compounds. Robustaflavone-4-methylether and delicaflavone showed the best cytotoxic activity on all the cell lines with IC50 (µM) values of 18.9 ± 2.1 and 22.7 ± 3.3 on A549, respectively. Of these biflavonoids, delicaflavone showed the most potent EGFR inhibitory activity with an 84% relative inhibition at 0.02 nM using erlotinib as a positive control. Robustaflavone-4-methylether showed a 78% inhibition at 0.15 nM. The docking scores obtained from the molecular docking study correlated with the kinase inhibition assay. Robustaflavone-4-methylether and delicaflavone had a docking score of 72.0 and 86.5, respectively. The inhibitory activity of delicaflavone seemed to be linked with the C2”=C3” and 3-O-4”’ linkage pattern. Thus, this study suggests that the structural features of these compounds could serve as a basis for developing new EGFR-TK inhibitors.

Keywords: anticancer, biflavonoids, EGFR, molecular docking, Selaginellaceae

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1629 Antitrypanosomal Activity of Stigmasterol: An in silico Approach

Authors: Mohammed Auwal Ibrahim, Aminu Mohammed


Stigmasterol has previously been reported to possess antitrypanosomal activity using in vitro and in vivo models. However, the mechanism of antitrypanosomal activity is yet to be elucidated. In the present study, molecular docking was used to decipher the mode of interaction and binding affinity of stigmasterol to three known antitrypanosomal drug targets viz; adenosine kinase, ornithine decarboxylase and triose phosphate isomerase. Stigmasterol was found to bind to the selected trypanosomal enzymes with minimum binding energy of -4.2, -6.5 and -6.6 kcal/mol for adenosine kinase, ornithine decarboxylase, and triose phosphate isomerase respectively. However, hydrogen bond was not involved in the interaction of stigmasterol with all the three enzymes, but hydrophobic interaction seemed to play a vital role in the binding phenomenon which was predicted to be non-competitive like type of inhibition. It was concluded that binding to the three selected enzymes, especially triose phosphate isomerase, might be involved in the antitrypanosomal activity of stigmasterol but not mediated via a hydrogen bond interaction.

Keywords: antitrypanosomal, in silico, molecular docking, stigmasterol

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1628 N₂O₂ Salphen-Like Ligand and Its Pd(II), Ag(I) and Cu(II) Complexes as Potentially Anticancer Agents: Design, Synthesis, Antimicrobial, CT-DNA Binding and Molecular Docking

Authors: Laila H. Abdel-Rahman, Mohamed Shaker S. Adam, Ahmed M. Abu-Dief, Hanan El-Sayed Ahmed


In this investigation, Cu(II), Pd(II) and Ag(I) complexes with the tetra-dentate DSPH Schiff base ligand were synthesized. The DSPH Schiff base and its complexes were characterized by using different physicochemical and spectral analysis. The results revealed that the metal ions coordinated with DSPH ligand through azomethine nitrogen and phenolic oxygen. Cu(II), Pd(II) and Ag(I) complexes are present in a 1:1 molar ratio. Pd(II) and Ag(I) complexes have square planar geometries while, Cu(II) has a distorted octahedral (Oh) geometry. All investigated complexes are nonelectrolytes. The investigated compounds were tested against different strains of bacteria and fungi. Both prepared compounds showed good results of inhibition against the selected pathogenic microorganism. Moreover, the interaction of investigated complexes with CT-DNA was studied via various techniques and the binding modes are mainly intercalative and grooving modes. Operating Environment MOE package was used to do docking studies for the investigated complexes to explore the potential binding mode and energy. Furthermore, the growth inhibitory effect of the investigated compounds was examined on some cancer cells lines.

Keywords: tetradentate, antimicrobial, CT-DNA interaction, docking, anticancer

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1627 Preventing Neurodegenerative Diseases by Stabilization of Superoxide Dismutase by Natural Polyphenolic Compounds

Authors: Danish Idrees, Vijay Kumar, Samudrala Gourinath


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1). The use of small molecules has been shown to stabilize the SOD1 dimer and preventing its dissociation and aggregation. In this study, we employed molecular docking, molecular dynamics simulation and surface plasmon resonance (SPR) to study the interactions between SOD1 and natural polyphenolic compounds. In order to explore the noncovalent interaction between SOD1 and natural polyphenolic compounds, molecular docking and molecular dynamic (MD) simulations were employed to gain insights into the binding modes and free energies of SOD1-polyphenolic compounds. MM/PBSA methods were used to calculate free energies from obtained MD trajectories. The compounds, Hesperidin, Ergosterol, and Rutin showed the excellent binding affinity in micromolar range with SOD1. Ergosterol and Hesperidin have the strongest binding affinity to SOD1 and was subjected to further characterization. Biophysical experiments using Circular Dichroism and Thioflavin T fluorescence spectroscopy results show that the binding of these two compounds can stabilize SOD1 dimer and inhibit the aggregation of SOD1. Molecular simulation results also suggest that these compounds reduce the dissociation of SOD1 dimers through direct interaction with the dimer interface. This study will be helpful to develop other drug-like molecules which may have the effect to reduce the aggregation of SOD1.

Keywords: amyotrophic lateral sclerosis, molecular dynamics simulation, surface plasmon resonance, superoxide dismutase

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1626 Revealing Potential Drug Targets against Proto-Oncogene Wnt10B by Comparative Molecular Docking

Authors: Shazia Mannan, Zunera Khalid, Hammad-Ul-Mubeen


Wingless type Mouse mammary tumor virus (MMTV) Integration site-10B (Wnt10B) is an important member of the Wnt protein family that functions as cellular messenger in paracrine manner. Aberrant Wnt10B activity is the cause of several abnormalities including cancers of breast, cervix, liver, gastric tract, esophagus, pancreas as well as physiological problems like obesity, and osteoporosis. The objective of this study was to determine the possible inhibitors against aberrant expression of Wnt10B in order to prevent and treat the physiological disorders associated with it. Wnt10B3D structure was predicted by using comparative modeling and then analyzed by PROCHECK, Verify3D, and Errat. The model having 84.54% quality value was selected and acylated to satisfy the hydrophobic nature of Wnt10B. For search of inhibitors, virtual screening was performed on Natural Products (NP) database. The compounds were filtered and ligand-based screening was performed using the antagonist for mouse Wnt-3A. This resulted in a library of 272 unique compounds having most potent drug like activities for Wnt-4. Out of the 271 molecules analyzed three small molecules ZINC35442871, ZINC85876388, and ZINC00754234 having activity against Wnt4 abbarent expression were found common through docking experiment of Wnt10B. It is concluded that the three molecules ZINC35442871, ZINC85876388, and ZINC00754234 can be considered as lead compounds for performing further drug designing experiments against aberrant Wnt expressions.

Keywords: Wnt10B inhibitors, comparative computational studies, proto-oncogene, molecular docking

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1625 Antiplasmodial Activity of Drimane Sesquiterpene Isolated from Warburgia salutaris

Authors: Mthokozisi Simelane


Background: Malaria remains a life-threatening disease in tropical regions despite the advances in the treatment of this disease, it still remains a significant burden as some parasites have become resistant to the currently available drugs. This has created a necessity for the development of alternative, more efficient antimalarial drugs. Warburgia salutaris is a traditional medicinal plant used in malaria treatment by Zulu traditional healers. Materials and methods: The W. salutaris stem-bark was extracted with dichloromethane and the compound was isolated through column chromatography. The compound was identified and characterized by spectroscopic analysis (1H NMR, 13C NMR, IR and MS) and the structure was also confirmed by x-ray crystallography. The anti-plasmodial activity (in vitro) was studied on NF54 Plasmodium falciparum strain (CQS). Cytotoxicity was measured using the MTT assay on HEK239 and HEPG2 cell lines. Docking of Mukaadial acetate was conducted in AutoDock Vina. Structural modifications were conducted in UCSF Chimera and molecular interactions examined in LigPlot. Results: The compound, Mukaadial Acetate showed appreciable inhibition (IC50 0.44±0.10 µg/ml) of the parasite growth and cytotoxicity activity of 0.124±0.109 and 0.199±0.083 (µg/ml) on HEK293 and HEPG2 cells respectively. Molecular docking revealed that Mukaadial Acetate binds to the purine, pyrophosphate and ribose binding sites of the PfHGXPRT with an optimum binding conformation and forms hydrogen bond, steric and hydrophobic interactions with the residues inhabiting the respective binding sites. Conclusion: It is apparent that W. salutaris contains components (including Mukaadial Acetate) that exhibit antimalarial activity. This study scientifically validates the use of this plant in folk medicine.

Keywords: plasmodium falciparum, molecular docking, antimalarial activity, PfHGXPRT, Warburgia salutaris, mukaadial acetate

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