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bioRxiv · 10.1101/2021.07.05.451101

Identification of potential carboxylic acid-containing drug candidate to design novel competitive NDM inhibitors: An in-silico approach comprising combined virtual screening and molecular dynamics simulation

Anbarasu, A.·Veeraraghavan, B.·Vasudevan, K.·Basu, S.·Arumugam, A.·Naha, A.·Ramaiah, S.
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Abstract

Metallo-{beta}-lactamases (MBLs) producing bacteria especially the ones with New Delhi metallo-beta-lactamase-1 (NDM-1) and its variants can potentially hydrolyse all the major {beta}-lactam antibiotics, ultimately escalating anti-microbial resistance world-wide. There is a dearth of approved inhibitors to combat NDM and other MBLs producing bacteria. Hence we focussed to find novel inhibitor(s) in-silico which can potentially suppress the activity of NDM/ MBLs. 2400 compounds were virtually screened to identify a promising carboxylic acid-containing compound (CID-53986787) analogous to NDM antagonist Captopril. Our lead compound can bind adjacent to the active site zinc ions (Zn1 and Zn2) in all highly resistant NDM variants. CID-53986787 possesses ~5-8% higher binding affinity than Captopril, exhibiting molecular interactions with crucial residues that can destabilize the hydrolytic activity of NDM. CID-53986787 was virtually evaluated to ascertain its safe pharmacological/ toxicity profile. Molecular dynamics simulation studies elucidated its stable interaction with the target protein (NDM-1).

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Anbarasu, A., Veeraraghavan, B., Vasudevan, K., Basu, S., Arumugam, A., Naha, A., Ramaiah, S.. 2021-07-05. Identification of potential carboxylic acid-containing drug candidate to design novel competitive NDM inhibitors: An in-silico approach comprising combined virtual screening and molecular dynamics simulation. https://doi.org/10.1101/2021.07.05.451101

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