Crystal structures and binding studies of atovaquone and its derivatives with cytochromebc1: a molecular basis for drug design

Abstract

Crystal structure of trans-atovaquone (antimalarial drug), its polymorph and its stereoisomer (cis) along with five other derivatives with different functional groups have been analyzed. Based on the conformational features of these compounds and the characteristics of the nature of intermolecular interactions, valuable insights into the atomistic details of protein–inhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular O–H⋯O hydrogen bond dimer motifs supported by surrogate weak interactions including C–H⋯O and C–H⋯Cl hydrogen bonds. The docking results of these molecules with cytochrome bc₁ show preferences to form N–H⋯O, O–H⋯O and O–H⋯Cl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of protein–ligand docking reported earlier based on mimicking experimental binding results of stigmatellin with cytochrome bc₁. The significance of subtle energy factors controlled by weak intermolecular interactions appears to play a major role in drug binding.