Investigating the bispecific lead compounds against methicillin-resistant Staphylococcus aureus SarA and CrtM using machine learning and molecular dynamics approach

Kareem M Younes; Amr S Abouzied; Ahmed Alafnan; Bader Huwaimel; Weam M A Khojali; Rami M Alzahrani

doi:10.1080/07391102.2023.2297012

Investigating the bispecific lead compounds against methicillin-resistant Staphylococcus aureus SarA and CrtM using machine learning and molecular dynamics approach

J Biomol Struct Dyn. 2023 Dec 26:1-18. doi: 10.1080/07391102.2023.2297012. Online ahead of print.

Authors

Kareem M Younes^{1

2}, Amr S Abouzied^{1

3}, Ahmed Alafnan⁴, Bader Huwaimel^{1

5}, Weam M A Khojali^{1

6}, Rami M Alzahrani⁷

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail, Saudi Arabia.
² Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, National Organization for Drug Control and Research (NODCAR), Giza, Egypt.
⁴ Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Saudi Arabia.
⁵ Medical and Diagnostic Research Center, University of Ha'il, Hail, Saudi Arabia.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Omdurman Islamic University, Omdurman, Sudan.
⁷ Department of Pharmaceutics, College of Pharmacy, Taif University, Taif, Saudi Arabia.

PMID: 38147401
DOI: 10.1080/07391102.2023.2297012

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious pathogen that has emerged as a serious global health concern over the past few decades. Staphylococcal accessory regulator A (SarA) and 4,4'-diapophytoene synthase (CrtM) play a crucial role in biofilm formation and staphyloxanthin biosynthesis. Thus, the present study used a machine learning-based QSAR model to screen 1261 plant-derived natural organic compounds in order to identify a medication candidate with both biofilm and virulence inhibitory potential. Additionally, the in-silico molecular docking analysis has demonstrated significant binding efficacy of the identified hit compound, that is 85137543, with SarA and CrtM when compared to the control compound, hesperidin. Post-MD simulation analysis of the complexes depicted strong binding of 85137543 to both SarA and CrtM. Moreover, 85137543 showed hydrogen bonding with the key residues of both proteins during docking (ALA138 of SarA and ALA134 of CrtM) and post-MD simulation (LYS273 of CrtM and ASN212 of SarA). The RMSD of 85137543 was stable and consistent when bound to both CrtM and SarA with RMSDs of 1.3 and 1 nm, respectively. In addition, principal component analysis and the free energy landscape showed stable complex formation with both proteins. Low binding free energy (ΔGTotal) was observed by 85137543 for SarA (-47.92 kcal/mol) and CrtM (-36.43 kcal/mol), which showed strong binding. Overall, this study identified 85137543 as a potential inhibitor of both SarA and CrtM in MRSA.Communicated by Ramaswamy H. Sarma.

Keywords: 4′-diapophytoene synthase); CrtM (4; Methicillin-resistant; SarA (Staphylococcal accessory regulator A); Staphylococcus aureus; plant-derived natural organic compounds.