Structure-Based Discovery of Potent Staphylococcus aureus Thymidylate Kinase Inhibitors by Virtual Screening

Abstract

Introduction: Multidrug-resistant bacteria are rapidly increasing worldwide, increasing antibiotic resistance. The exploitation, misuse, overuse, and decrease of the therapeutic potential of currently available antibiotics have resulted in the development of resistance against bacteria. As the most common bacterial pathogen in humans, Staphylococcus aureus can cause many adverse health effects. In fighting multidrug-resistant Staphylococcus aureus, scientists have identified an extremely relevant target - SaTMPK. SaTMPK is essential for DNA synthesis, which, in turn, is necessary for the replication and cell division of bacteria.

Objective: To perform multi-stage screening using the ZINC database, followed by molecular docking, ADMET profiling, molecular dynamics simulations, and energy calculations.

Methods: Based on the similar pharmacophoric characteristics of existing SaTMPK crystal structures, a model of interaction-based pharmacophores was developed. We then performed molecular docking studies on the positive hits obtained from the pharmacophore screening. Compounds that exhibited good molecular interactions within the SaTMPK binding sites were further evaluated using in-silico ADMET profiling.

Results: In a multi-stage screening campaign, three compounds were shortlisted that exhibited physicochemical characteristics suitable for human administration.

Conclusion: The findings from this study should contribute to in vitro and in vivo studies for clinical applications.

Keywords: Antibiotic resistance; MD simulation; MM/PBSA.; Staphlococcus aureus; pharmacophore; thymidylate kinase; virtual screening.