Blind docking simulations of benzothiazoles on triosephosphate isomerase

Abstract

Selective inhibition of the activity of the glycolytic enzyme triosephosphate isomerase from Trypanosoma cruzi (TcTIM) as opposed to human TIM (hTIM) has been critical for drug design studies on Chagas disease. The aim of this docking study is to uncover the binding modes of benzothiazoles, reported as effective inhibitors of TcTIM. Blind dockings of five benzothiazoles are performed on both TcTIM and hTIM by using the Lamarckian genetic algorithm of AutoDock v4.0. Protein flexibility is incorporated via docking to multiple, distinct conformations that are obtained from extended molecular dynamics simulations. The clusters that fall within 1 kcal/mol of the lowest energy poses from docking are analyzed for determination of alternative binding sites. The inhibitors mostly bind to the tunnel-shaped region formed at the interface of the subunits in TcTIM, whereas other sites are preferred by the non-inhibitors. Moreover, blind dockings to equilibrated conformers of TcTIM monomer indicate no distinct tendency of inhibitors for binding to the interface region that becomes solvent accessible upon dissociation to monomers. Thus, the tunnel-shaped cavity on the TcTIM dimer interface is the most distinct site for the action of inhibitors, consistent with previous studies. Interactions of strong inhibitors at the interface at the TcTIM interface include interactions with aromatic residues (Phe75, Tyr102 and Tyr103) and cation-interactions (with Arg71, Arg99 and Lys113). In addition, multiple hydrogen bonds between the sulfonate group (present only in inhibitors) and residues Asn67, Thr70, Arg99 and Lys113 are found to be specific in the case of the strong inhibitors. Further blind dockings of sulfonate-free derivatives of inhibitors and a sulfonate-added derivative of a non-inhibitor on TcTIM have indicated that the sulfonate group aids the correct positioning of benzothiazoles in the tunnel-shaped cavity. The inhibitors docked on hTIM conformers show a non-selective behavior for the interface of hTIM dimer, which does not present an accessible tunnel-shaped cavity as TcTIM. Binding sites other than the interface region are also reported for TcTIM and hTIM.