Search results for: pharmacophore

Authors: Harish Rajak, Preeti Patel

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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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Authors: Romasa Qasim, G. M. Sayedur Rahman, Nahid Hasan, M. Shazzad Hosain

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Millions of people worldwide suffer from Hepatitis C, one of the fatal diseases. Interferon (IFN) and ribavirin are the available treatments for patients with Hepatitis C, but these treatments have their own side-effects. Our research focused on the development of an orally taken small molecule drug targeting the proteins in Hepatitis C Virus (HCV), which has lesser side effects. Our current study aims to the Pharmacophore based drug development of a specific small molecule anti-viral drug for Hepatitis C Virus (HCV). Drug designing using lab experimentation is not only costly but also it takes a lot of time to conduct such experimentation. Instead in this in silico study, we have used computer-aided techniques to propose a Pharmacophore-based anti-viral drug specific for the protein domains of the polyprotein present in the Hepatitis C Virus. This study has used homology modeling and ab initio modeling for protein 3D structure generation followed by pocket identification in the proteins. Drug-able ligands for the pockets were designed using de novo drug design method. For ligand design, pocket geometry is taken into account. Out of several generated ligands, a new Pharmacophore is proposed, specific for each of the protein domains of HCV.

Keywords: pharmacophore-based drug design, anti-viral drug, in-silico drug design, Hepatitis C virus (HCV)

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Authors: Harish Rajak, Preeti Patel

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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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Authors: S. Roy, R. Rekha, K. Sriram, G. Subhadra, R. Johana

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Cardiovascular disease remains a leading cause of death in most industrialized countries. Many chemical drugs are available in the market which targets different receptor proteins related to cardiovascular diseases. Of late the traditional herbal drugs are safer when compared to chemical drugs because of its side effects. However, many herbal remedies used in treating cardiovascular diseases have not undergone scientific assessment to prove its pharmacological activities. There are many natural compounds, nature derived and Natural product mimic compounds are available which are in the market as approved drug. In the most of the cases drug activity at the molecular level are not known. Here we have categorized those compounds with our experimental compounds in different classes based on the structural similarity and physicochemical properties, using a tool, Chemmine and has attempted to understand the mechanism of the action of a experimental compound, which are clustered with Simvastatin, Lovastatin, Mevastatin and Pravastatin. Target protein molecule for Simvastatin, Lovastatin, Mevastatin and Pravastatin is HMG-CoA reductase, so we concluded that the experimental compound may be able to bind to the same target. Molecular docking and atomic interaction studies with simvastatin and our experimental compound were compared. A pharmacophore modeling was done based on the experimental compound and HMG-CoA reductase inhibitor.

Keywords: molecular docking, physicochemical properties, pharmacophore modeling structural similarity, pravastatin

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Authors: Somdutt Mujwar, Kamal Raj Pardasani

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Cholera pandemics are caused by facultative pathogenic Vibrio cholera bacteria persisting in the countries having warmer climatic conditions as well as the presence of large water bodies with huge amount of organic matter, it is responsible for the millions of deaths annually. Presently the available therapy for cholera is Oral Rehydration Therapy (ORT) with an antibiotic drug. Excessive utilization of life saving antibiotics drugs leads to the development of resistance by the infectious micro-organism against the antibiotic drugs resulting in loss of effectiveness of these drugs. Also, many side effects are also associated with the use of these antibiotic drugs. This riboswitch is explored as an alternative drug target for Vibrio cholera bacteria to overcome the problem of drug resistance as well as side effects associated with the antibiotics drugs. The bacterial riboswitch is virtually screened with 24407 legends to get possible drug candidates. The 10 ligands showing best binding with the riboswitch are selected to design a pharmacophore, which can be utilized to design lead molecules by using the phenomenon of bioisosterism.

Keywords: cholera, drug design, ligand, riboswitch, pharmacophore

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Authors: Ankur Chaudhuri, Sibani Sen Chakraborty

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In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

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Authors: Dmitry Yu. Korulkin, Raissa A. Muzychkina

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Currently to treat infectious diseases bioactive substances of plant origin having fewer side effects than synthetic medicines and medicines similar to natural components of a human body by the structure and action, become very important. One of the groups of secondary metabolites of the plants - alkaloids can be related the number of the most promising sources of medicines of plant origin. Currently, the structure of more than 7500 compounds has been identified. Analyzing the scope of research in the field of chemistry, pharmacology and technology of alkaloids, we can make a conclusion about that there is no system approach during the research of relation structure-activity on different groups of these substances. It is connected not only with a complex structure of their molecules, but also with insufficient information on the nature of their effect on organs, tissues and other targets in organism. The purpose of this research was to identify pharmacophore groups in the structure of alkaloids of endemic Polygonum L. plants growing in Kazakhstan responsible for their antiviral action. To isolate alkaloids pharmacopoeian methods were used. Antiviral activity of alkaloids of Polygonum L. plants was researched in the Institute of Microbiology and Virology of the Ministry of Education and Science of the Republic of Kazakhstan. Virus-inhibiting properties of compounds were studies in experiments with ortho- and paramyxoviruses on the model of chick-embryos. Anti-viral properties were determined using ‘screening test’ method designed to neutralization of a virus at the amount of 100EID50 with set concentrations of medicines. The difference of virus titer compared to control group was deemed as the criterion of antiviral action. It has been established that Polygonum L. alkaloids has high antiviral effect to influenza and parainfluenza viruses. The analysis of correlation of the structure and antiviral activity of alkaloids allowed identifying the main pharmacophore groups, among which the most important are glycosidation, the presence of carbonyl and hydroxyl groups, molecular weight and molecular size.

Keywords: alkaloids, antiviral, bioactive substances, isolation, pharmacophore groups, Polygonum L.

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Authors: Amarjyoti Das Mahapatra, Umesh Kumar, Bhaskar Datta

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A pseudo peptide can mimic the biological or structural properties of natural peptides. They have become an increasing attention in medicinal chemistry because of their interesting advantages like more bioavailability and less biodegradation than compare to the physiologically active native peptides which increase their therapeutic applications. Many biologically active compounds contain urea as functional groups, and they have improved pharmacokinetic properties because of their bioavailability and metabolic stability. Recently we have reported a single-step synthesis of sulfonyl urea and sulfonyltriuret from sulfonyl chloride and sodium cyanate. But the yield of sulfonyltriuret was less around 40-60% because of the formation of other products like sulfonamide and sulfonylureas. In the present work, we mainly focused on the selective synthesis of sulfonyltriuret using tetrabutylammonium cyanate and sulfonyl chloride. More precisely, we are interested in the controlled synthesis of oligomeric urea mainly sulfonyltriuret as a new class of pseudo peptide and their application as protease modulators. The distinctive architecture of these molecules in the form of their pseudo-peptide backbone offers promise as a potential pharmacophore. The synthesized molecules have been screened on trypsin enzyme, and we observed that these molecules are the efficient modulator of trypsin enzyme.

Keywords: pseudo peptide, pharmacophore, sulfonyltriuret, trypsin

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Authors: Pritika Ramharack, Mahmoud E. S. Soliman

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The re-emerging Zika virus is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus already been linked to irreversible chronic central nervous system (CNS) conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA-approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of Zika virus Methyltransferase and RNA-dependent RNA polymerase. This in silico “per-residue energy decomposition pharmacophore” virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.

Keywords: NS5 protein inhibitors, per-residue decomposition, pharmacophore model, virtual screening, Zika virus

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Authors: Junie B. Billones, Maria Constancia O. Carrillo, Voltaire G. Organo, Stephani Joy Y. Macalino, Inno A. Emnacen, Jamie Bernadette A. Sy

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One of the major interferences in the Philippines’ tuberculosis control program is the widespread prevalence of Mtb strains that are resistant to known drugs, such as the MDR-TB (Multi Drug Resistant Tuberculosis) and XDR-TB (Extensively Drug Resistant Tuberculosis). Therefore, there is a pressing need to search for novel Mtb drug targets in order to be able to combat these drug resistant strains. The enzyme 7,8-diaminopelargonic acid aminotransferase enzyme, or more commonly known as BioA, is one such ideal target, as it is known that humans do not possess this enzyme. BioA primarily plays a key role in Mtb’s lipid biosynthesis pathway; more specifically in the synthesis of the enzyme cofactor biotin. In this study, structure-based pharmacophore screening, docking, and ADMET evaluation of compounds obtained from the DrugBank chemical database were performed against the MtbBioA enzyme. Results of the screening, docking, ADMET, and TOPKAT calculations revealed that out of the 6,516 compounds in the library, only 7 compounds indicated more favorable binding energies as compared to the enzyme’s known inhibitor, amiclenomycin (ACM), as well as good solubility and toxicity properties. Moreover, out of these 7 compounds, Molecule 6 exhibited the best solubility and toxicity properties. In the future, these lead compounds may then be subjected to bioactivity assays in vitro or in vivo for further evaluation of its therapeutic efficacy.

Keywords: 7, 8-diaminopelargonic acid aminotransferase, BioA, pharmacophore, molecular docking, ADMET, TOPKAT

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

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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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Authors: Imran Muhammad

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The main cause of infectious disease in the modern world is Mycobacterium Tuberculosis (MT). To combat tuberculosis, new and efficient drugs are an urgent need in the modern world. Schif bases are potent for their biological pharmacophore activity. Thus we selected different Vanillin-based Schiff bases for their binding activity against target enzymes of Mycobacterium tuberculosis that is (DprE1 (decaprenyl phosphoryl-β-D-ribose 2′-epimerase), and DNA gyrase subunit-A), using molecular docking. We evaluate the inhibition potential, interaction, and binding mode of these compounds with the target enzymes.

Keywords: schiff bases, tuberculosis, DNA gyrase, DprE1, docking

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Authors: Jineetkumar Gawad, Chandrakant Bonde

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Tuberculosis (TB) is a major worldwide concern whose control has been exacerbated by HIV, the rise of multidrug-resistance (MDR-TB) and extensively drug resistance (XDR-TB) strains of Mycobacterium tuberculosis. The interest for newer and faster acting antitubercular drugs are more remarkable than any time. To search potent compounds is need and challenge for researchers. Here, we tried to design lead for inhibition of Decaprenyl phosphoryl-β-D-ribose 2′-epimerase (DprE1) enzyme. Arabinose is an essential constituent of mycobacterial cell wall. DprE1 is a flavoenzyme that converts decaprenylphosphoryl-D-ribose into decaprenylphosphoryl-2-keto-ribose, which is intermediate in biosynthetic pathway of arabinose. Latter, DprE2 converts keto-ribose into decaprenylphosphoryl-D-arabinose. We had a selection of 23 compounds from azaindole series for computational study, and they were drawn using marvisketch. Ligands were prepared using Maestro molecular modeling interface, Schrodinger, v10.5. Common pharmacophore hypotheses were developed by applying dataset thresholds to yield active and inactive set of compounds. There were 326 hypotheses were developed. On the basis of survival score, ADRRR (Survival Score: 5.453) was selected. Selected pharmacophore hypotheses were subjected to virtual screening results into 1000 hits. Hits were prepared and docked with protein 4KW5 (oxydoreductase inhibitor) was downloaded in .pdb format from RCSB Protein Data Bank. Protein was prepared using protein preparation wizard. Protein was preprocessed, the workspace was analyzed using force field OPLS 2005. Glide grid was generated by picking single atom in molecule. Prepared ligands were docked with prepared protein 4KW5 using Glide docking. After docking, on the basis of glide score top-five compounds were selected, (5223, 5812, 0661, 0662, and 2945) and the glide docking score (-8.928, -8.534, -8.412, -8.411, -8.351) respectively. There were interactions of ligand and protein, specifically HIS 132, LYS 418, TRY 230, ASN 385. Pi-pi stacking was observed in few compounds with basic Imidazo [4,5-b] pyridine ring. We had basic azaindole ring in parent compounds, but after glide docking, we received compounds with Imidazo [4,5-b] pyridine as a basic ring. That might be the new lead in the process of drug discovery.

Keywords: DprE1 inhibitors, in silico drug designing, imidazo [4, 5-b] pyridine, lead, tuberculosis

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Authors: Fatima Doganc, Hakan Goker

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Benzimidazole moiety is an important pharmacophore and privileged structure for the medicinal chemists, since it exhibits various important biological activities. Some clinically used drugs have benzimidazole moiety, such as omeprazole, astemizole, albendazole and domperidone. 2-(4-tert-Butylphenyl)benzimidazole, is a PGC-1α transcriptional regulator shown to have beneficial effects in diabetic mice. We planned to modify the structure of this compound for developing new antidiabetic drug candidates. Hence, a series of guanidino or amidino, benzo/pyrido/pyrimidino-imidazole derivatives were freshly prepared. Mass, 1H-NMR, 13C-NMR, 2D-NMR spectroscopy techniques were used for the new derivatives to clarify their structures and their purity was controlled through the elemental analysis. Antidiabetic activity studies of the synthesized compounds are under the investigation.

Keywords: antidiabetic agents, benzimidazole, imidazopyridine, imidazopyrimidine

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Authors: Ram Sharma, Esha Chatterjee, Santosh Kumar Guru, Kunal Nepali

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A tractable anti-lung cancer agent was identified via the installation of a Ring C expanded synthetic analogue of the alkaloid vasicinone [7,8,9,10-tetrahydroazepino[2,1-b] quinazolin-12(6H)-one (TAZQ)] as a surface recognition part in the HDAC inhibitory three-component model. Noteworthy to mention that the candidature of TAZQ was deemed suitable for accommodation in HDAC inhibitory pharmacophore as per the results of the fragment recruitment process conducted by our laboratory. TAZQ was pinpointed through the fragment screening program as a synthetically flexible fragment endowed with some moderate cell growth inhibitory activity against the lung cancer cell lines, and it was anticipated that the use of the aforementioned fragment to generate hydroxamic acid functionality (zinc-binding motif) bearing HDAC inhibitors would boost the antitumor efficacy of TAZQ. Consistent with our aim of applying epigenetic targets to the treatment of lung cancer, a strikingly potent anti-lung cancer scaffold (compound 6) was pinpointed through a series of in-vitro experiments. Notably, the compounds manifested a magnificent activity profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80 - 0.96 µM), and the effects were found to be mediated through preferential HDAC6 inhibition (IC50 = 12.9 nM). In addition to HDAC6 inhibition, the compounds also elicited HDAC1 and HDAC3 inhibitory activity with an IC50 value of 49.9 nM and 68.5 nM, respectively. The HDAC inhibitory ability of compound 6 was also confirmed from the results of the western blot experiment that revealed its potential to decrease the expression levels of HDAC isoforms (HDAC1, HDAC3, and HDAC6). Noteworthy to mention that complete downregulation of the HDAC6 isoform was exerted by compound 6 at 0.5 and 1 µM. Moreover, in another western blot experiment, treatment with hydroxamic acid 6 led to upregulation of H3 acK9 and α-Tubulin acK40 levels, ascertaining its inhibitory activity toward both the class I HDACs and Class II B HDACs. The results of other assays were also encouraging as treatment with compound 6 led to the suppression of the colony formation ability of A549 cells, induction of apoptosis, and increase in autophagic flux. In silico studies led us to rationalize the results of the experimental assay, and some key interactions of compound 6 with the amino acid residues of HDAC isoforms were identified. In light of the impressive activity spectrum of compound 6, a pH-responsive nanocarrier (hyaluronic acid-compound 6 nanoparticles) was prepared. The dialysis bag approach was used for the assessment of the nanoparticles under both normal and acidic circumstances, and the pH-sensitive nature of hyaluronic acid-compound 6 nanoparticles was confirmed. Delightfully, the nanoformulation was devoid of cytotoxicity against the L929 mouse fibroblast cells (normal settings) and exhibited selective cytotoxicity towards the A549 lung cancer cell lines. In a nutshell, compound 6 appears to be a promising adduct, and a detailed investigation of this compound might yield a therapeutic for the treatment of lung cancer.

Keywords: HDAC inhibitors, lung cancer, scaffold, hyaluronic acid, nanoparticles

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Authors: Jana Tchekalarova, Stela Georgieva, Petia Peneva, Petar Todorov

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In the present study, a series of bioconjugates of N-modified hemorphine analogs containing second pharmacophore cinnamic acids (CA) or caffeic acid (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorometric analysis and in vivo anticonvulsant activity in mice were conducted on the compounds. The three CA (H4-CA, H5-CA, and H7-CA) and three KA (H4-KA, H5-KA, and H7-KA)-conjugated hemorphine derivatives showed dose-dependent anticonvulsant activity in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate was the only compound that suppressed clonic seizures at the lowest dose of 0.5 µg/mouse in the scPTZ test. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. The peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA hemorphine peptides can be used as a background for developing hemorphin-related analogs with anticonvulsant activity. Acknowledgments: This study is funded by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0002, "BiOrgaMCT".

Keywords: hemorphins, SPSS, caffeic/cinnamic acid, anticonvulsant activity, electrochemistry, fluorimetry

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Authors: Brian J. Graham, Ronald T. Raines

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The presence of a nearly vacant p orbital on boron endows boronic acids with unique abilities as a catalyst and ligand. An organocatalytic process has been developed for the conversion of biomass-derived sugars to 5-hydroxymethylfurfural, which is a platform chemical. Specifically, 2-carboxyphenylboronic acid (2-CPBA) has been shown to be an optimal catalyst for this process, promoting the desired transformation in the absence of metals. The attributes of 2-CPBA as a catalyst led to additional investigations of its structure and reactivity. 2-CPBA was found to exist as a cyclized benzoxaborolone adduct rather than a free carboxylic acid. This cyclization has profound consequences for the oxidative stability of the boronic acid. Stereoelectronic effects within the oxaborolone ring destabilize the oxidation transition state by reducing electron donation from the cyclic oxygen to the developing p orbital on boron. That leads to a 10,000-fold increase in oxidative stability while maintaining the normal reactivity of boronic acids toward diols (e.g., carbohydrates) and nucleophiles in proteins while also presenting numerous hydrogen-bond accepting and donating groups. Thus, benzoxaborolones are useful in catalysis, chemical biology, medicinal chemistry, and allied fields.

Keywords: bioisosteres, boronic acid, catalysis, oxidative stability, pharmacophore, stereoelectronic effects

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Authors: Jana Tchekalarova, Stela Georgieva, Petia Peneva, Petar Todorov

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In the present study, a series of bioconjugates of N-modified hemorphine analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetrical analysis and in vivo anticonvulsant activity in mice were conducted on the compounds. The three CA acids (H4-CA, H5-CA, and H7-CA) and three KA acids (H4-KA, H5-KA, and H7-KA)-conjugated hemorphine derivatives showed dose-dependent anticonvulsant activity in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate was the only compound that suppressed clonic seizures at the lowest dose of 0.5 µg/mouse in the scPTZ test. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. The peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA hemorphine peptides can be used as a background for developing hemorphin-related analogs with anticonvulsant activity. Acknowledgements: This study is funded by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0002, "BiOrgaMCT".

Keywords: hemorphins, caffeic/cinnamic acid, anticonvulsant activity, electrochemistry, fluorimetry

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Authors: Uzma Saqib, Mirza S. Baig

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Myeloid differentiation primary response protein 88 (MYD88) has long been considered a central player in the inflammatory pathway. Recent studies clearly suggest that it is an important therapeutic target in inflammation. On the other hand, a recent study on the interaction between the orphan nuclear receptor (Nur77) and p38α, leading to increased lipopolysaccharide-induced hyperinflammatory response, suggests this binary complex as a therapeutic target. In this study, we have designed inhibitors that can inhibit both MYD88 and Nur77 at the same time. Since both MYD88 and Nur77 are an integral part of the pathways involving lipopolysaccharide-induced activation of NF-κB-mediated inflammation, we tried to target both proteins with the same library in order to retrieve compounds having dual inhibitory properties. To perform this, we developed a homodimeric model of MYD88 and, along with the crystal structure of Nur77, screened a virtual library of compounds from the traditional Chinese medicine database containing ~61,000 compounds. We analyzed the resulting hits for their efficacy for dual binding and probed them for developing a common pharmacophore model that could be used as a prototype to screen compound libraries as well as to guide combinatorial library design to search for ideal dual-target inhibitors. Thus, our study explores the identification of novel leads having dual inhibiting effects due to binding to both MYD88 and Nur77 targets.

Keywords: drug design, Nur77, MYD88, inflammation

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Authors: Harish Rajak, Swati Singh

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A series of novel pyrimidine based semicarbazone were designed and synthesized on the basis of semicarbazone based pharmacophoric model to satisfy the structural prerequisite crucial for antiepileptic activity. The semicarbazones based pharmacophoric model consists of following four essential binding sites: (i) An aryl hydrophobic binding site with halo substituent; (ii) A hydrogen bonding domain; (iii) An electron donor group and (iv) Another hydrophobic-hydrophilic site controlling the pharmacokinetic features of the anticonvulsant. The aryl semicarbazones has been recognized as a structurally novel class of compounds with remarkable anticonvulsant activity. In the present study, all the test semicarbazones were subjected to molecular docking using Glide v5.8. Some of the compounds were found to interact with ARG192, GLU270 and THR353 residues of 1OHV protein, present in GABA-AT receptor. The chemical structures of the synthesized molecules were characterized by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. The neurotoxicity was evaluated in mice by the rotorod test. The attempts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study confirmed that the pharmacophore model with four binding sites is essential for antiepileptic activity.

Keywords: pyrimidine, semicarbazones, anticonvulsant activity, neurotoxicity

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Authors: Nidhi Chadha, A. K. Tiwari, Marilyn D. Milton, Anil K. Mishra

Abstract:

Translocator protein (18 kDa) TSPO is highly expressed during microglia activation in neuroinflammation. Although a number of PET ligands have been developed for the visualization of activated microglia, one of the advantageous approaches is to develop potential optical imaging (OI) probe. Our study involves computational screening, synthesis and evaluation of TSPO ligand through various imaging modalities namely PET/SPECT/Optical. The initial computational screening involves pharmacophore modeling from the library designing having oxo-benzooxazol-3-yl-N-phenyl-acetamide groups and synthesis for visualization of efficacy of these compounds as multimodal imaging probes. Structure modeling of monomer, Ala147Thr mutated, parallel and anti-parallel TSPO dimers was performed and docking analysis was performed for distinct binding sites. Computational analysis showed pattern of variable binding profile of known diagnostic ligands and NBMP via interactions with conserved residues along with TSPO’s natural polymorphism of Ala147→Thr, which showed alteration in the binding affinity due to considerable changes in tertiary structure. Preliminary in vitro binding studies shows binding affinity in the range of 1-5 nm and selectivity was also certified by blocking studies. In summary, this skeleton was found to be potential probe for TSPO imaging due to ease in synthesis, appropriate lipophilicity and reach to specific region of brain.

Keywords: TSPO, molecular modeling, imaging, docking

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Authors: N. Gopal, K. Jaasminerjiit, L. Z. Xiang

Abstract:

Quinazoline-4(3H)-one ring system has been consistently regarded as promising privileged structural icon owing to its pharmacodynamic versatility in many of its synthetic derivatives as well as in several naturally occurring alkaloids. The literature reveals that 2nd & 3rd positions of the quinazolin-4(3H)-one pharmacophore are the target for substitution with other moieties. On the other hand, sulphanilamide derivatives and isatin moiety also displayed valuable biological activities. Hence, it was thought worthwhile to study the effects of three pharmacophoric moieties like quinazolinone, sulphanilamide and isatin in a single molecule for the better analgesic activity with lower toxicity. Series of novel 2,3-disubstituted quinazolin-4(3H)-one derivatives have been synthesised from the intermediate Schiff base of 2-(4’-substitutedphenyl)-3-[(N-2-oxoindolin-3-ylidene)-4”-sulphonamidophenyl]-quinazolin-4(3H)-one derivatives, which was prepared from reacting 2-(substituted phenyl)-4H-benzo[d][1,3]-oxazin-4-one with sulphanilamide. The required benzoxazinone derivatives were prepared by reacting anthranilic acid with benzoyl chloride. All the compounds structure was characterised by using H1 NMR, IR and Mass spectroscopy. The intermediate Schiff base and final Mannich base compounds were evaluated for their analgesic activity by acetic acid-induced writhing method at the dose of 25mg/kg, 50 mg/kg, and 100 mg/kg (bw) and Diclofenac (25mg/kg of body weight) will be used as the reference drugs. From the results of the study, it has been observed that final Mannich base showed a better analgesic activity when compared to the parent Schiff bases, it was found that compound substituted with N-methyl piperazine at 1st position of the indole nucleus of the final quinazolinone derivatives (GA4B1) i.e. 2-(4’-methoxy phenyl)-3-[4-(N-(1-N-methyl piperazine amine) methyl-2-oxo indoilin-3-ylidene] benzenesulfonyl quinazolin-4(3H)-one increases the analgesic activity and among the synthesised compounds, GA4B1 exhibited quite superior analgesic activity. The remaining Schiff bases and Mannich base derivatives exhibited moderate analgesic activity. All the compounds showed a dose dependent activity. None of the synthesised compound showed ulcer index whereas the standard drug, diclofenac [25 mg/kg (bw)] showed significantly higher gross ulcer index values.

Keywords: analgesic activity, isatin, mannich base, quinazolin-4(3H)-one

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Authors: Junie B. Billones, Maria Constancia O. Carrillo, Voltaire G. Organo, Stephani Joy Y. Macalino, Inno A. Emnacen, Jamie Bernadette A. Sy

Abstract:

The drug discovery and development process is generally known to be a very lengthy and labor-intensive process. Therefore, in order to be able to deliver prompt and effective responses to cure certain diseases, there is an urgent need to reduce the time and resources needed to design, develop, and optimize potential drugs. Computer-aided drug design (CADD) is able to alleviate this issue by applying computational power in order to streamline the whole drug discovery process, starting from target identification to lead optimization. This drug design approach can be predominantly applied to diseases that cause major public health concerns, such as tuberculosis. Hitherto, there has been no concrete cure for this disease, especially with the continuing emergence of drug resistant strains. In this study, CADD is employed for tuberculosis by first identifying a key enzyme in the mycobacterium’s metabolic pathway that would make a good drug target. One such potential target is the lipoate protein ligase B enzyme (LipB), which is a key enzyme in the M. tuberculosis metabolic pathway involved in the biosynthesis of the lipoic acid cofactor. Its expression is considerably up-regulated in patients with multi-drug resistant tuberculosis (MDR-TB) and it has no known back-up mechanism that can take over its function when inhibited, making it an extremely attractive target. Using cutting-edge computational methods, compounds from AnalytiCon Discovery Natural Derivatives database were screened and docked against the LipB enzyme in order to rank them based on their binding affinities. Compounds which have better binding affinities than LipB’s known inhibitor, decanoic acid, were subjected to in silico toxicity evaluation using the ADMET and TOPKAT protocols. Out of the 31,692 compounds in the database, 112 of these showed better binding energies than decanoic acid. Furthermore, 12 out of the 112 compounds showed highly promising ADMET and TOPKAT properties. Future studies involving in vitro or in vivo bioassays may be done to further confirm the therapeutic efficacy of these 12 compounds, which eventually may then lead to a novel class of anti-tuberculosis drugs.

Keywords: pharmacophore, molecular docking, lipoate protein ligase B (LipB), ADMET, TOPKAT

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Authors: Akanksha Bhatnagar, Sandhya Kortegare, Felice Elefant

Abstract:

Context: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive cognitive decline and memory loss. The cause of AD is not fully understood, but it is thought to be caused by a combination of genetic, environmental, and lifestyle factors. One of the hallmarks of AD is the loss of neurons in the hippocampus, a brain region that is important for memory and learning. This loss of neurons is thought to be caused by a decrease in histone acetylation, which is a process that regulates gene expression. Research Aim: The research aim of the study was to develop mall molecule compounds that can enhance the activity of Tip60, a histone acetyltransferase that is important for memory and learning. Methodology/Analysis: The researchers used in silico structural modeling and a pharmacophore-based virtual screening approach to design and synthesize small molecule compounds strongly predicted to target and enhance Tip60’s HAT activity. The compounds were then tested in vitro and in vivo to assess their ability to enhance Tip60 activity and rescue cognitive deficits in AD models. Findings: The researchers found that several of the compounds were able to enhance Tip60 activity and rescue cognitive deficits in AD models. The compounds were also developed to cross the blood-brain barrier, which is an important factor for the development of potential AD therapeutics. Theoretical Importance: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Data Collection: The study collected data from a variety of sources, including in vitro assays and animal models. The in vitro assays assessed the ability of compounds to enhance Tip60 activity using histone acetyltransferase (HAT) enzyme assays and chromatin immunoprecipitation assays. Animal models were used to assess the ability of the compounds to rescue cognitive deficits in AD models using a variety of behavioral tests, including locomotor ability, sensory learning, and recognition tasks. The human clinical trials will be used to assess the safety and efficacy of the compounds in humans. Questions: The question addressed by this study was whether Tip60 HAT activators could be developed as therapeutic agents for AD. Conclusions: The findings of this study suggest that Tip60 HAT activators have the potential to be developed as therapeutic agents for AD. The compounds are specific to Tip60, which suggests that they may have fewer side effects than other HDAC inhibitors. Additionally, the compounds are able to cross the blood-brain barrier, which is a major hurdle for the development of AD therapeutics. Further research is needed to confirm the safety and efficacy of these compounds in humans.

Keywords: Alzheimer's disease, cognition, neuroepigenetics, drug discovery

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