Title: De novo drug design, pharmacophore search and molecular docking for inhibitors to treat TB and HIV co-infection

Authors: Satheeshkumar Sellamuthu; Ashok Kumar; Sushil Kumar Singh

Addresses: Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India ' Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India ' Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India

Abstract: Novel molecules were designed as possible inhibitors of ATP synthase through de novo drug design, but were not drug-like molecules. Hence, ZINC database was searched for drug-like molecules from the common pharmacophore of the designed molecules. A total of 472 hits were obtained, among them, ZINC39552534, ZINC39371747, and ZINC38959526 produced better docking than the standard drug Bedaquiline. The vulnerability of TB and HIV co-infection has necessitated the search for inhibitors effective against both the diseases. Hence, the hits obtained were further screened for possible interaction with HIV reverse transcriptase. ZINC63941671, ZINC05858010, and ZINC05857787 were found better over the standard drug Rilpivirine, but their interaction was least against ATP synthase. Further, ZINC38959526 (lead against ATP synthase) and ZINC05858010 (lead against reverse transcriptase) share some common chemical features and based on this, new hybrid molecules were designed to inhibit both the targets. The possibility of hERG toxicity was also checked to eliminate unwanted cardiotoxicity.

Keywords: ATP synthase inhibitors; de novo drug design; HIV; hERG toxicity; molecular docking; pharmacophore search; reverse transcriptase; tuberculosis; ZINC database.

DOI: 10.1504/IJCBDD.2019.101056

International Journal of Computational Biology and Drug Design, 2019 Vol.12 No.3, pp.230 - 250

Received: 05 May 2017
Accepted: 20 May 2018
Published online: 23 Jul 2019 *

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