Atom-based 3D-QSAR, molecular docking, DFT, and simulation studies of acylhydrazone, hydrazine, and diazene derivatives
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ORIGINAL RESEARCH
Atom-based 3D-QSAR, molecular docking, DFT, and simulation studies of acylhydrazone, hydrazine, and diazene derivatives as IN-LEDGF/p75 inhibitors Umesh Panwar 1 & Sanjeev Kumar Singh 1 Received: 16 April 2020 / Accepted: 25 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Since HIV-1 integrase makes use of host genome machinery to accomplish the replication process, where LEDGF/p75 (a cellular cofactor) executes in the lentiviral integration process by interacting with integrase. Thus, the integrase-LEDGF/p75 interaction has become an interesting drug target in developing a potent agent. The purpose of the present study is to understand the inhibition mechanism with a structural basis of developed integrase inhibitors against viral infection. Herein, the computational approaches like atom-based 3D-QSAR, docking, MM/GBSA, DFT, and MDS were applied on a series of acylhydrazone, hydrazine, and diazene derivatives as integrase inhibitors. The developed 3D-QSAR model resulted in great predictive ability with training set (R2 = 0.98, SD = 0.07) and for test set (Q2 = 0.89, RMSE = 0.14, Pearson R = 0.90). The binding mode of interaction and involvement of energy on most and least active compounds into the LEDGF/p75 binding pocket of integrase were explored. We also observed that the predicted 3D-QSAR model has a good level of potential support by means of favorable and unfavorable regions of hydrogen bond donor, acceptor (electron-withdrawing), and hydrophobic groups for most active compound 7. This approach helps further to design anti-HIV inhibitors based on binding mode interaction and stability analysis. Keywords IN-LEDGF/p75 . 3D-QSAR . Docking . MM/GBSA . DFT . Simulation
Introduction The major causative agent of acquired immune deficiency syndrome (AIDS) is the human immunodeficiency virus type 1 (HIV-1), which has cost millions of lives in recent two decades [1, 2]. Presently, the discovery of anti-viral therapeutics for the inhibition of HIV-1 replication cycle still remains a challenging task in drug discovery. Since, some of the potent inhibitors have been identified against HIV’s three major drug targets: reverse transcriptase, protease, and integrase, which play a vital role in viral infection [3]. Among these, HIV-1 integrase plays a pivotal role in the amalgamation of the DNA Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01628-3) contains supplementary material, which is available to authorized users. * Sanjeev Kumar Singh [email protected] 1
Computer Aided Drug Design and Molecular Modelling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu 630 004, India
of the virus into the genome of host during the early stage of retroviral replication. Integrase is a highly conserved and wellcharacterized protein encoded at the 3′ end of HIV Pol gene. IN consists of three structural domains such as a NTD (a zincbinding N-terminal domain), CCD (a central RNAse H-like
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