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Open AccessArticle

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

1
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, Casilla 747, Talca 3460000, Chile
2
Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Autopista Concepción–Talcahuano 7100, Talcahuano 4260000, Chile
3
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción 4030000, Chile
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6133; https://doi.org/10.3390/ijms20246133
Received: 18 November 2019 / Revised: 30 November 2019 / Accepted: 3 December 2019 / Published: 5 December 2019
(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2020)
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). View Full-Text
Keywords: Pseudomonas aeruginosa elastase; N-alpha-mercaptoacetyl dipeptides; 3D-QSAR; docking; interaction fingerprints Pseudomonas aeruginosa elastase; N-alpha-mercaptoacetyl dipeptides; 3D-QSAR; docking; interaction fingerprints
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MDPI and ACS Style

Velázquez-Libera, J.L.; Murillo-López, J.A.; F. de la Torre, A.; Caballero, J. Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies. Int. J. Mol. Sci. 2019, 20, 6133.

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