New Active HIV‐1 Protease Inhibitors Derived from 3‐Hexanol: Conformation Study of the Free Inhibitors in Crystalline State and in Complex with the Enzyme

Abstract

Four novel linear non‐peptidic HIV‐1 protease inhibitors derived from 2,5‐diamino‐1,6‐diphenyl‐3‐hexanol were synthesized and characterized. All of them exhibit tight binding to HIV‐1 protease, with inhibition constants Ki in the range 20 pm–5 nm. The investigated inhibitors were crystallized, and their crystal structures were determined by X‐ray diffraction. In all cases, the conformations found in the crystalline state differ significantly from the conformations obtained by computational docking of the inhibitor in the binding cleft of native HIV‐1 protease. Owing to the prevalence of hydrophobic substituents in all these inhibitors, the conformational mobility in water solution is restricted to their compact forms. The spectrum of low‐energy conformations in solution dramatically changes during the formation of inhibitor crystals (phenyl ring stacking as a leading motif) or during the formation of a complex with HIV‐1 protease (elongated conformation suitable to fit the enzyme pockets as a factor responsible for tight binding). High conformational flexibility and low conformational stress in the molecules of these inhibitors most likely increase their biological activity in comparison with more rigid compounds.