Pharmacophore modeling, 3D-QSAR, docking, and molecular dynamics simulation on topoisomerase IV inhibitors of wild type Staphylococcus aureus

Abstract

Staphylococcus aureus is a gram-positive bacterium. It is a foremost cause of skin and respiratory infections, endocarditis, osteomyelitis, Ritter’s disease, and bacteraemia. Topoisomerase enzyme is involved in preventing or correcting topological problems of overwinding or underwinding occurring in DNA before replication process. An exhaustive molecular modeling studies that includes pharmacophore modeling, ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics simulation, and ADME calculations were performed on isothiazoloquinolones derivatives which are reported as effective inhibitors against topoisomerase IV of wild type S. aureus. In pharmacophore modeling by using pharmacophore alignment and scoring engine (PHASE) a five-point model (AHHRR.3) was generated with existing compounds having statistical significant as correlation coefficient (R 2 = 0.954), cross-validation coefficient (Q 2 = 0.650), and F value of 130.5. Ligand-based 3D-QSAR study was applied using comparative molecular field analysis (CoMFA) with Q 2 = 0.616, R 2 = 0.989, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 = 0.510, R 2 = 0.995. The predictive ability of this model was determined using a test set of molecules that gave acceptable predictive correlation (R 2 Pred) values 0.55 and 0.56 for CoMFA and CoMSIA, respectively. Docking and molecular dynamic simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed pharmacophore models and docking methods provide guidance to design enhanced activity molecules.