New 1(2H)-phthalazinone derivatives as potent nonpeptidic HIV-1 protease inhibitors: molecular docking studies, molecular dynamics simulation, oral bioavailability and ADME prediction

Abstract

Molecular docking simulations of compounds 1–7, the newly synthesised 1(2H)-phthalazinone derivatives with N-(dimethylamino)ethyl pendant arm, as potent inhibitors of HIV-1 protease (HIV-1 PR) were performed. The results of calculations show that compounds 1–7 can form stable complexes with HIV-1 PR and their inhibitory action is mainly based on combination of intermolecular hydrogen bonds and ionic interactions between flexible cationic ammonium moiety of ligands and deprotonated carboxylic residues Asp25 and Asp29 of the target receptor. Molecular dynamics calculation in explicit water environment of the best ranked complex of compound 3 with HIV-1 PR reveals its high stability with conservation of strong salt bridge interactions during all simulation time. Per-residue decomposition of the binding free energy of HIV-1 PR complex with compound 3 calculated with the MM-PBSA method shows electrostatic and van der Waals interactions as the main favourable components. Estimated oral bioavailability and calculated absorption, distribution, metabolism and excretion (ADME) descriptors, namely, intestinal absorption, aqueous solubility and blood–brain barrier penetration, for compounds 1–7 indicate their good pharmacokinetic profile in humans after oral administration. Enthalpically favourable contribution of ligand–receptor salt bridge interactions and hydrogen bonds to binding free energy in calculated complexes of compounds 1–7 with HIV-1 PR also suggests a potent feature to combat a drug resistance to HIV-1 PR inhibitors.