Anti-HIV potential of diarylpyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors: design, synthesis, docking, TOPKAT analysis and molecular dynamics simulations

Abstract

All chemicals were bought from Sigma Aldrich Chemical Company, USA and E. Merck India Ltd, India. All chemical reactions were carried out in oven dried apparatus and solvents used were dried and distilled. Column chromatography was carried out on silica gel (100-200 mess). Reactions were monitored on TLC, using silica gel 60F254 aluminium plates and visualized under ultraviolet light at 254 nm. Melting points were recorded on electro thermal apparatus. NMR spectra were recorded on BRUKER-AV400 spectrometer (Bruker Co., Faellanden, Switzerland) in DMSO-d6 ( 1 H at 400 MHz and 13 C at 100 MHz). Chemical shifts (δ) are expressed in parts per million (ppm) and J (Coupling constant)values in Hz.Multiplicities are indicated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), m (multiplet) and br (broad spectrum). Mass spectra were recorded on Micromass Q-Tof (ESI-HRMS). The elemental analyses were performed for all compounds on a Perkin-Elmer 240-C analyses equipment. S1.2. General synthesis of diarylpyrimidine derivatives (1-6)A mixture of different types of aromatic amines (3.37 mmol) and K2CO3 (3.37 mmol) in 10 mL DMF was stirred at room temperature for 15 min. 2, 4-dichloropyrimidine (3.37 mmol) was added and the mixture was stirred at reflux for 4-6 h. Reaction was monitored on TLC for its completion. The solvent was evaporated and residue was partitioned between water

Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α within-vitroeffective drug ivermectin

“…Molecular Dynamics (MD) simulations have great significance to analyze the internal motions, conformational changes, stability, etc., of protein-ligand complexes ( Sen Gupta et al, 2020 ; Singh et al, 2020 ). Utilizing the MD trajectories generated, RMSD, RMSF, and R g were computed and the results are discussed below.…”

“…Apart from allowing to assess the equilibration, quality of the run and convergence of MD trajectories, RMSD is useful to investigate the stability of a protein in complex ( Sen Gupta et al, 2020 ; Singh et al, 2020 ). A larger RMSD value is indicative of the lower stability of a protein complex.…”

“…The binding free energy ( ΔG bind ) has been computed with MM/PBSA (Kumari et al, 2014 ), which is considered as a very efficient and reliable approach to study crucial molecular recognition processes (Kumari et al, 2014 ; Open Source Drug Discovery Consortium, 2014; Sen Gupta et al, 2020 ; Singh et al, 2020 ). Figure 6 and Table S2 ( supplementary material ) reveal that the RdRp-Ivermectin complex has ΔG bind (-187.3 kJ mol −1 ) twice as high as the Helicase-Ivermectin complex (-94.6 kJ mol −1 ), even better than the Importin-α-Ivermectin complex (-156.7 kJ mol −1 ).…”

“…For binding free energy ( ΔG bind ) from MD trajectory, widely used molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) was adapted (Kumari et al, 2014 ; Sen Gupta et al, 2020 ; Singh et al, 2020 ). ΔG bind in a solvent medium was calculated as follows:…”

Binding Mechanism and Structural Insights into the Identified Protein Target of Covid-19 with In-Vitro Effective Drug Ivermectin

“…conformational changes, stability, etc. of protein-ligand complexes [15][16] . Utilizing the MD trajectories generated, RMSD, RMSF, and Rg were computed and the results are discussed below.…”