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Identification of small molecule inhibitors of ALK2: a virtual screening, density functional theory, and molecular dynamics simulations study

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Abstract

Bone morphogenetic proteins (BMPs) are a family of more than 30 ligands and several receptors, such as activin like kinases (ALKs) and bone morphogenetic protein receptor (BMPR). Physiological significance of these proteins lies in their prominent role during homeostasis, apoptosis, tissue remodeling, embryonic patterning, and normal development. Fibrodysplasia ossificans progressive (FOP) is one among several other diseases caused by impaired BMP signaling. FOP is caused by the pathogenicity of activating mutation of ALK2. In order to treat FOP, a search for good inhibitors of ALK2 based on dorsomorphin and LDN substitution, which in essence is a ligand based search of inhibitors, is in progress. Contributing to this area of research we identified several lead molecules based on protein structure using virtual screening. After virtual screening of a huge library of small molecules and ab initio calculation of selected molecules for drug efficacy, we did molecular dynamic simulation of lead molecules and protein complexes. We identified five potential drug molecules that show very stable binding on the same binding site as LDN-213844. We also ranked these lead molecules based on MM/PBSA binding energy. This study provides a basis to think beyond the pyrimidine nucleus of dorsomorphin/LDN and design new chemical derivatives for effective treatment of FOP.

Small molecule inhibitors of ALK2

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Acknowledgments

This research work has been carried out in the Department of Chemistry, Aligarh Muslim University, U.P., India. Supercomputing facility has been provided from BRAF, CDAC, Pune, India for our computational work. We are also grateful to IUAC, New Delhi, India for giving us the supercomputing facility.

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  1. Department of Chemistry, Aligarh Muslim University, Aligarh, U.P., 202002, India

    Tasneem Kausar & Shahid M. Nayeem

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  1. Tasneem Kausar
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Correspondence to Shahid M. Nayeem.

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Kausar, T., Nayeem, S.M. Identification of small molecule inhibitors of ALK2: a virtual screening, density functional theory, and molecular dynamics simulations study. J Mol Model 24, 262 (2018). https://doi.org/10.1007/s00894-018-3789-2

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