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Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents

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Abstract

Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces many challenges such as lengthy treatment protocols, drug resistance and toxicity. In the present work, mycolic acid methyl transferase (MmaA1), a protein involved in the maturation of mycolic acids in the biochemical pathway of the Mycobacterium, was studied for novel drug discovery. The homology model of the MmaA1 protein was built and validated by using computational techniques. The MmaA1 protein has 286 amino acid residues consisting of 10 α-helices and 7 β-sheets. The active site of the MmaA1 protein was identified using CASTp, SiteMap and PatchDock. Virtual screening studies were performed with two small molecule ligand databases: Asinex synergy and Diverse_Elite_Gold_Platinum databases having a total of 43,446 molecules and generated 1,30,814 conformers against the predicted and validated active site of the MmaA1 protein. Binding analysis showed that the residues ASP 19, PHE 22, TRP 30, TYR 32, TRP 74 and ALA 77 of MmaA1 protein have consistent interactions with the ligands. The hit ligands were further filtered by in silico ADME properties to eliminate potentially toxic molecules. Of the top 10 molecules, 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl) benzamide was synthesised and screened for in vitro anti-TB activity against Mtb H37Rv using MABA assay. The compound and its intermediates exhibited good in vitro anti-TB activity which can be taken up for future lead optimisation studies.

Graphical abstract

Structure based virtual screening study was performed using a validated homology model against small molecules from two virtual compound libraries. Synthesised the lead compound 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl)benzamide obtained from virtual screening. In vitro activity against Mtb H37Rv has given a promising result.

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Acknowledgements

The author HV acknowledges Department of Science and Technology (DST), Government of India, for financial support under the Women Scientist Scheme (WOS-A) vide reference no. SR/WOS-A/CS-1031/2014. The authors HV, VM, KKM, RV, RM and UV acknowledge the Principal and Head, Department of Chemistry, University College of Sciences, Osmania University, Hyderabad, India, for providing the facilities to carry out this work. The authors HV and MMK acknowledge the Principal, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, India, for providing the facilities to carry out this work.

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Authors and Affiliations

  1. Pharmaceutical Chemistry Research Lab, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, 530003, India

    Hymavathi Veeravarapu & Murali Krishna Kumar Muthyala

  2. Molecular Modelling Research Lab, Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, India

    Hymavathi Veeravarapu, Vasavi Malkhed, Kiran Kumar Mustyala, Rajender Vadija, Ramesh Malikanti & Uma Vuruputuri

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  1. Hymavathi Veeravarapu
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Veeravarapu, H., Malkhed, V., Mustyala, K.K. et al. Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents. Mol Divers 25, 351–366 (2021). https://doi.org/10.1007/s11030-020-10107-0

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