2. Academic Validation
  3. 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

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

  • Comput Biol Chem. 2023 Oct:106:107910. doi: 10.1016/j.compbiolchem.2023.107910.
Ritika Srivastava 1,  Sunil K Gupta 2,  Farha Naaz 2,  Parth Sarthi Sen Gupta 3,  Madhu Yadav 2,  Vishal Kumar Singh 2,  Saroj Kumar Panda 4,  Satyaranjan Biswal 4,  Malay Kumar Rana 4,  Satish Kumar Gupta 5,  Dominique Schols 6,  Ramendra K Singh 7
Affiliations

Affiliations

  • 1 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.
  • 2 Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India.
  • 3 School of Biosciences and Bioengineering, D Y Patil International University, Akurdi, Pune, India.
  • 4 Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India.
  • 5 National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
  • 6 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • 7 Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India. Electronic address: rksinghsrk@gmail.com.
PMID: 37422940 DOI: 10.1016/j.compbiolchem.2023.107910
Abstract

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 IC50 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.

Keywords

ADMET; Docking; HIV; MM/PBSA; Molecular dynamics; Pyrimidines.

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