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

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.