Exploring antiviral potency of N-1 substituted pyrimidines against HIV-1 and other DNA/RNA viruses: Design, synthesis, characterization, ADMET analysis, docking, molecular dynamics and biological activity.

Autor: Srivastava R; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India; Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India., Gupta SK; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India., Naaz F; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India., Sen Gupta PS; School of Biosciences and Bioengineering, D Y Patil International University, Akurdi, Pune, India., Yadav M; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India., Singh VK; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India., Panda SK; Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India., Biswal S; Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India., Rana MK; Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India., Gupta SK; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India., Schols D; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., Singh RK; Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India. Electronic address: rksinghsrk@gmail.com.
Jazyk: angličtina
Zdroj: Computational biology and chemistry [Comput Biol Chem] 2023 Oct; Vol. 106, pp. 107910. Date of Electronic Publication: 2023 Jun 27.
DOI: 10.1016/j.compbiolchem.2023.107910
Abstrakt: A novel series of pyrimidine derivatives, bearing modified benzimidazoles at N-1 position, has been designed, synthesized and screened as NNRTIs against HIV and as broad-spectrum antiviral agents. The molecules were screened against different HIV targets using molecular docking experiment. The docking results indicated that the molecules interacted well with the residues Lys101, Tyr181, Tyr188, Trp229, Phe227 and Tyr318 present in NNIBP of HIV-RT protein, formed quite stable complexes and, thus, behaved as probable NNRTIs. Among these compounds, 2b and 4b showed anti-HIV activity with IC 50 values as 6.65 µg/mL (SI = 15.50) and 15.82 µg/mL (SI = 14.26), respectively. Similarly, compound 1a showed inhibitory property against coxsackie virus B4 and compound 3b against different viruses. Molecular dynamics simulation results unequivocally demonstrated the higher stability of the complex HIV-RT:2b than the HIV-RT:nevirapine complex. The MM/PBSA-based binding free energy (-) 114.92 kJ/mol of HIV-RT:2b complex in comparison to that of HIV-RT:nevirapine complex (-) 88.33 kJ/mol, further demonstrated the higher binding strength of 2b and thus, established the potential of compound 2b as a lead molecule as an HIV-RT inhibitor.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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