In silico and structural investigation of sulfonamides targeting VraSR two component system in methicillin-resistant Staphylococcus aureus

Abstract

Drug-resistant Staphylococcus aureus strains are global health concerns. Several studies have shown that these strains can develop defences against cell wall antibiotics such as β-lactams, glycopeptides and daptomycin which target cell wall biosynthesis. The coordination of these responses have been associated with two component system (TCS) regulated by histidine kinase protein (VraS) and its cognate regulator VraR which influences the target DNA upon signal recognition. Computer-based screening methods, predictions and simulations have emerged as more efficient and quick ways to identify promising new compound leads from large databases against emerging drug targets thus allowing prediction of small select set of molecules for further validations. These combined approaches conserve valuable time and resources. Due to methicillin resistance, sulfonamide-derivative medications have been found to be effective treatment strategy to treat S. aureus infections. The current study used ligand-based virtual screening (LBVS) to identify powerful sulfonamide derivative inhibitors from an antibacterial compound library against VraSR signaling components, VraS and VraR. We identified promising sulfonamide derivative [compound 5: (4-[(1-{[(3,5-Dimethoxyphenyl)Carbamoyl]Methyl}-2,4-Dioxo-1,2,3,4-Tetrahydroquinazolin-3-Yl)Methyl]-N-[(Furan-2-Yl)Methyl]Benzamide)] with reasonable binding parameters of −31.38 kJ/mol and ΔG_bind score of −294.32 kJ/mol against ATP binding domain of sensor kinase VraS. We further identified four compounds N1 (PCID83276726), N3 (PCID83276757), N9 (PCID3672584), and N10 (PCID20900589) against VraR DNA binding domain (VraR_C) with ΔG_bind energies of −190.27, −237.54, −165.21, and −190.88 kJ/mol, respectively. Structural and simulation analyses further suggest their stable interactions with DNA interacting residues and potential to disrupt DNA binding domain dimerization; therefore, it is prudent to further investigate and characterize them as VraR dimer disruptors and inhibit other promoter binding site. Interestingly, the discovery of drugs that target VraS and VraR may open new therapeutic avenues for drug-resistant S. aureus. These predictions based on screening, simulations and binding affinities against VraSR components hold promise for opening novel therapeutic avenues against drug-resistant S. aureus and present opportunities for repositioning efforts. These efforts aim to create analogs with enhanced potency and selectivity against two-component signaling systems that significantly contribute to virulence in MRSA or VRSA. These analyses contribute valuable insights into potential avenues for combating antibiotic-resistant S. aureus through computationally driven drug discovery strategies.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug-resistant S. aureus
• in silico screening
• two-component system
• VraS
• VraR_C
• antibacterial compound library
• sulfonamides derivatives

Acknowledgments

The authors acknowledge the support of the Internet of Things (IoT) and Data Communication Lab; Multiscale Simulation and Research Center (MSRC) Manipal University Jaipur for computational calculations. Abhishek Kumar Verma acknowledges Ramdas Pai scholarship [(DoR/RPSA/2021-22/12-21/25(05)] from Manipal University Jaipur.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors contribution

Formal analysis, investigation- AKV, SKS; writing-review and editing- AKV, SKS; conceptualization, supervision, funding acquisition- SKS. Authors have read and agreed to the published version of the manuscript.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Additional information

Funding

PI's laboratory is funded through DST-SERB grant CRG/2020/002008. Department of Biosciences, Manipal University Jaipur is supported by DST-FIST (DST/2022/1012), Govt. of India.