Predicting the binding modes of SRI-3072 inhibitor to mycobacterium tuberdulosis FtsZ using docking and molecular dynamics simulation

Abstract

To overcome the problem of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (Mtb) for tuberculosis (TB) treatment, there is an urgent need to identify new target and lead compound which have potential to develop as new anti-tuberculosis (anti-TB) drug. We are interested in protein that plays a crucial role in bacterial cell division, filamentous temperature-sensitive protein Z (FtsZ). The 2-alkoxycarbonylaminopyridine SRI-3072 has been reported as an anti-FtsZ agent that inhibits GTPase activity, FtsZ polymerization and growth of M. tuberculosis without any perturbation on tubulin. In this study, the structural insight into binding mode of SRI-3072 in MtbFtsZ was predicted using molecular modeling. The 3D-structure of MtbFtsZ (PDB code 1RLU) after deleting GTP--S was used throughout this study. Two plausible binding sites of MtbFtsZ i.e. nucleotide-binding pocket and analogous Taxol-binding cleft were detected and applied for docking of SRI-3072. Base on top-ranked docking score and binding energy, pose-25 and pose-3 were selected to represent the binding modes of SRI-3072 in nucleotide-binding pocket and analogous Taxol-binding pocket of MtbFtsZ, respectively. The binding mode analyses of two stable complexes were deduced from molecular dynamics simulation. The types of interactions (e.g. hydrophobic, hydrogen bond) and interaction energies (i.e. van der Waals and electrostatic terms) were identified to allocate possible binding mode of SRI-3072. The results show that the preferable binding mode of SRI-3072 is in nucleotide-binding site as observed by the presence of strong binding energy and interactions. Our study provides structural information of MtbFtszSRI-3072 complex to be used as a tool for virtual screening, discovery and design of new anti-TB in the future.