Anti-HIV potential of diarylpyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors: Design, synthesis, docking, TOPKAT analysis and molecular dynamics simulations
Creators: name: Vishal K. Singh
name: Ritika Srivastava
name: Parth Sarthi Sen Gupta
name: Farha Naaz
name: Himani Chaurasia
name: Mishra, Richa
name: Rana, Malay Kumar
name: Ramendra K. Singh
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biophysics
subject: Biochemistry
subject: Neuroscience
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: Cancer
subject: Hematology
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: 60506 Virology

description: In view of the low toxicity of NNRTIs in comparison to NRTIs, a new series of diarylpyrimidine derivatives has been designed as NNRTIs against HIV-1. <i>In silico</i> studies using DS 3.0 software have shown that these compounds behaved as NNRTIs while interacting at the allosteric site of HIV-RT. The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Tyr181, Tyr318 and π- interactions with Tyr181, Tyr188, Phe227 and Trp229 amino acid residues located in the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-RT protein. The intended molecules have shown high binding affinity with HIV-1 RT, analogous to standard drug molecule - etravirine. TOPKAT results confirmed that the designed compounds were found to be less toxic than the reference drug. Further, employing molecular dynamics simulations, the complexes of the best screened compound 6 and etravirine with the HIV-1 RT protein were analyzed by calculating the RMSD, RMSF, R<sub>g</sub>, number of hydrogen bonds, principal components of the coordinates, molecular mechanics-Poisson-Boltzmann surface area-based binding free energy and their decomposition for different interactions. The analysis demonstrated the higher stability of compound 6 than the standard drug etravirine with HIV-1 RT. The interactions like hydrogen-bonding, van-der-Waals, electrostatic and the solvent accessible surface energy have favorable contributions to the complex stability. Thus, the shortlisted designed compound has great promise as a potential inhibitor against HIV-1 RT. HighlightsNew diarylpyrimidine derivatives have been designed as potential anti-HIV agents.The compounds were docked at the allosteric site of HIV-RT protein (PDB ID: 3MEC) to study the stability of protein-ligand complex.Docking studies indicated the stable ligand-protein complexes of all designed compounds.The TOPKAT protocol in DS 3.0 software was used to evaluate the toxicity of the designed diarylpyrimidine derivatives.Molecular Dynamics studies were performed on best screened compound. New diarylpyrimidine derivatives have been designed as potential anti-HIV agents. The compounds were docked at the allosteric site of HIV-RT protein (PDB ID: 3MEC) to study the stability of protein-ligand complex. Docking studies indicated the stable ligand-protein complexes of all designed compounds. The TOPKAT protocol in DS 3.0 software was used to evaluate the toxicity of the designed diarylpyrimidine derivatives. Molecular Dynamics studies were performed on best screened compound.