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Article

A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics

1
College of Pharmacy, Jinan University, Guangzhou 511436, China
2
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
3
Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(14), 8000; https://doi.org/10.3390/ijms25148000 (registering DOI)
Submission received: 17 June 2024 / Revised: 16 July 2024 / Accepted: 18 July 2024 / Published: 22 July 2024
(This article belongs to the Section Molecular Informatics)

Abstract

RhlR plays a key role in the quorum sensing of Pseudomonas aeruginosa. The current structure–activity relationship (SAR) studies of RhlR inhibitors mainly focus on elucidating the functional groups. Based on a systematic review of previous research on RhlR inhibitors, this study aims to establish a systematic, hierarchical screening model for RhlR inhibitors. We initially established a database and utilized principal component analysis (PCA) to categorize the inhibitors into two classes. Based on the training set, pharmacophore models were established to elucidate the structural characteristics of ligands. Subsequently, molecular docking, molecular dynamics simulations, and the calculation of binding free energy and strain energy were performed to validate the crucial interactions between ligands and receptors. Then, the screening criteria for RhlR inhibitors were established hierarchically based on ligand structure characteristics, ligand–receptor interaction, and receptor affinity. Test sets were finally employed to validate the hierarchical virtual screening model by comparing it with the current SAR studies of RhlR inhibitors. The hierarchical screening model was confirmed to possess higher accuracy and a true positive rate, which holds promise for subsequent screening and the discovery of active RhlR inhibitors.
Keywords: Quorum sensing; RhlR; SAR; virtual screening; pharmacophore modeling; molecular docking; molecular dynamics Quorum sensing; RhlR; SAR; virtual screening; pharmacophore modeling; molecular docking; molecular dynamics

Share and Cite

MDPI and ACS Style

Du, J.; Li, J.; Wen, J.; Liu, J.; Xiao, H.; Zhang, A.; Yang, D.; Sun, P.; Zhou, H.; Xu, J. A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics. Int. J. Mol. Sci. 2024, 25, 8000. https://doi.org/10.3390/ijms25148000

AMA Style

Du J, Li J, Wen J, Liu J, Xiao H, Zhang A, Yang D, Sun P, Zhou H, Xu J. A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics. International Journal of Molecular Sciences. 2024; 25(14):8000. https://doi.org/10.3390/ijms25148000

Chicago/Turabian Style

Du, Jiarui, Jiahao Li, Juqi Wen, Jun Liu, Haichuan Xiao, Antian Zhang, Dongdong Yang, Pinghua Sun, Haibo Zhou, and Jun Xu. 2024. "A Systematic Hierarchical Virtual Screening Model for RhlR Inhibitors Based on PCA, Pharmacophore, Docking, and Molecular Dynamics" International Journal of Molecular Sciences 25, no. 14: 8000. https://doi.org/10.3390/ijms25148000

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