De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study

Balasaheb Shinde, Pooja, Bhowmick, Shovonlal, Alfantoukh, Etidal, Patil, Pritee Chunarkar, Wabaidur, Saikh Mohammad, Chikhale, Rupesh V ORCID: and Islam, Md Ataul (2020) De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study. Computational Biology and Chemistry, 88. ISSN 1476-9271

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In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novodrug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase.

Item Type: Article
Uncontrolled Keywords: de novo design,hiv-1 integrase,mm-pbsa,molecular docking,molecular dynamics,virtual screening,structural biology,biochemistry,organic chemistry,computational mathematics,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1315
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 25 Jun 2020 00:49
Last Modified: 22 Oct 2022 06:22
DOI: 10.1016/j.compbiolchem.2020.107319


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