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Computational Design of Inhibitory Agents of BMP-Noggin Interaction to Promote Osteogenesis

Authors: Shaila Ahmed, Raghu Prasad Rao Metpally, Sreedhara Sangadala, Boojala Vijay B Reddy

Abstract:

Bone growth factors, such as Bone Morphogenic Protein-2 (BMP-2) have been approved by the FDA to replace grafting for some surgical interventions, but the high dose requirement limits its use in patients. Noggin, an extracellular protein, blocks the effect of BMP-2 by binding to BMP. Preventing the BMP-2/noggin interaction will help increase the free concentration of BMP-2 and therefore should enhance its efficacy to induce bone formation. The work presented here involves computational design of novel small molecule inhibitory agents of BMP-2/noggin interaction, based on our current understanding of BMP-2, and its known putative ligands (receptors and antagonists). A successful acquisition of such an inhibitory agent of BMP-2/noggin interaction would allow clinicians to reduce the dose required of BMP-2 protein in clinical applications to promote osteogenesis. The available crystal structures of the BMPs, its receptors, and the binding partner noggin were analyzed to identify the critical residues involved in their interaction. In presenting this study, LUDI de novo design method was utilized to perform virtual screening of a large number of compounds from a commercially available library against the binding sites of noggin to identify the lead chemical compounds that could potentially block BMP-noggin interaction with a high specificity.

Keywords: Transforming growth factor-beta, Bone morphogenic proteins, Noggin, LUDI de novo design method, CAP small molecules.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1055621

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