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Gene. 2019 Feb 1;693:114-126. doi: 10.1016/j.gene.2019.01.029. [Epub ahead of print]

Drug repurposing against arabinosyl transferase (EmbC) of Mycobacterium tuberculosis: Essential dynamics and free energy minima based binding mechanics analysis.

Author information

1
School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India; Department of Biotechnology, TERI School of Advanced Studies, Plot No. 10, Vasant Kunj Institutional Area, Vasant Kunj, New Delhi, 110070, India.
2
Department of Biotechnology, TERI School of Advanced Studies, Plot No. 10, Vasant Kunj Institutional Area, Vasant Kunj, New Delhi, 110070, India. Electronic address: pallavi.somvanshi@terisas.ac.in.
3
School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: agrover@jnu.ac.in.

Abstract

Arabinosyl tranferases (embA, embB, embC) are the key enzymes responsible for biogenesis of arabinan domain of arabinogalactan (AG) and lipoarabinomannan (LAM), two major heteropolysaccharide constituents of the peculiar mycobacterial cell envelope. EmbC is predominantly responsible for LAM synthesis and has been commonly associated with Ethambutol resistance. We have screened the FDA library against EmbC to reposition a drug better than Ethambutol with higher binding affinity to Embc. High throughput virtual screening followed by extra precision docking using Glide gave two best leads i.e. Terlipressin and Amikacin with docking score of -11.39 kcal/mol and -10.71 kcal/mol, respectively. Binding mechanics of the selected drugs was elucidated through long range molecular dynamics simulations (100 ns) using binding free energy rescoring, essential dynamics and free energy minima based approaches, thus revealing the most stable binding modes of Terlipressin with EmbC. Our study establishes the EmbC binding potential of the repurposed drugs Terlipressin and Amikacin.

KEYWORDS:

Antitubercular; Arabinosyl transferase; Drug repurposing; EmbC; Free energy landscape

PMID:
30716439
DOI:
10.1016/j.gene.2019.01.029

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