Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies.

José Luis Velázquez-Libera,Alexander F De La Torre,Julio Caballero,Juliana Andrea Murillo-López

doi:10.3390/ijms20246133

Abstract

The zinc metallopeptidase Pseudomonas elastase (LasB) is a virulence factor of Pseudomonas aeruginosa (P. aeruginosa), a pathogenic bacterium that can cause nosocomial infections. The present study relates the structural analysis of 118 N-alpha-mercaptoacetyl dipeptides (NAMdPs) as LasB inhibitors. Field-based 3D-QSAR and molecular docking methods were employed to describe the essential interactions between NAMdPs and LasB binding sites, and the chemical features that determine their differential activities. We report a predictive 3D-QSAR model that was developed according to the internal and external validation tests. The best model, including steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic fields, was found to depict a three-dimensional map with the local positive and negative effects of these chemotypes on the LasB inhibitory activities. Furthermore, molecular docking experiments yielded bioactive conformations of NAMdPs inside the LasB binding site. The series of NAMdPs adopted a similar orientation with respect to phosphoramidon within the LasB binding site (crystallographic reference), where the backbone atoms of NAMdPs are hydrogen-bonded to the LasB residues N112, A113, and R198, similarly to phosphoramidon. Our study also included a deep description of the residues involved in the protein–ligand interaction patterns for the whole set of NAMdPs, through the use of interaction fingerprints (IFPs).

Highlights

Nosocomial infections— known as hospital acquired infections—are general or localized infectious processes in organs or anatomical regions, acquired by patients during hospitalization or through visits to other local health care centers
These poses were first compared to the phosphoramidon inhibitor that was taken as a reference (Protein Data Bank (PDB) code 3DBK), since it was the only crystallized compound with a structure similar to that of N-alpha-mercaptoacetyl dipeptides (NAMdPs)
A set of 118 NAMdP inhibitors was studied by using 3D-quantitative structure–activity relationship (QSAR) modeling and molecular docking

Summary

Introduction

Nosocomial infections— known as hospital acquired infections—are general or localized infectious processes in organs or anatomical regions, acquired by patients during hospitalization or through visits to other local health care centers. These undesired infections are considered to be a big global problem due to their social and economic impact [1]. The ongoing abuse of antibiotics to treat nosocomial infections has led to the problem of multidrug resistance [1], which is one of the major challenges of antimicrobial discovery [2,3,4,5]. Research is currently directed to seek specific antimicrobial agents focused on the action mechanisms of virulence factors [9]

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Results

Conclusion