Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

Abstract

The search for new antibacterial agents that could decrease bacterial resistance is a subject in continuous development. Gram-negative and Gram-positive bacteria possess a group of metalloproteins belonging to the MEROPS peptidase (M4) family, which is the main virulence factor of these bacteria. In this work, we used the previous results of a computational biochemistry protocol of a series of ligands designed in silico using thermolysin as a model for the search of antihypertensive agents. Here, thermolysin from Bacillus thermoproteolyticus, a metalloprotein of the M4 family, was used to determine the most promising candidate as an antibacterial agent. Our results from docking, molecular dynamics simulation, molecular mechanics Poisson–Boltzmann (MM-PBSA) method, ligand efficiency, and ADME-Tox properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicate that the designed ligands were adequately oriented in the thermolysin active site. The Lig783, Lig2177, and Lig3444 compounds showed the best dynamic behavior; however, from the ADME-Tox calculated properties, Lig783 was selected as the unique antibacterial agent candidate amongst the designed ligands.

Integral Evaluation of Neutral Endopeptidase Inhibitors as Possible Antihypertensive Agents by Means Molecular Mechanics, Free Energy Calculation and Adme-Tox Properties

“…This complex has been the most stable of all, considering a comprehensive analysis of the results obtained so far. Our results agree with previous works obtained with this same compound but using another M4 family metalloprotein similar to Neutral Endopeptidase [29,58]. Analyzing the free energy decomposition (Tab.…”

Valeriana pilosa Roots Essential Oil: Chemical Composition, Antioxidant Activities, and Molecular Docking Studies on Enzymes Involved in Redox Biological Processes

“…In addition to displaying a best affinity for both proteins, the six molecules of the VPEO constituents have strong ligand binding to the protein, as shown by their low K d values. Regarding LE values, they are in the range of 0.47 and 0.51 kcal·mol −1 , compared to LE values greater than 0.3 kcal·mol −1 required to be considered as a reference [ 61 ]. According to such descriptors, compounds 24 , 25 , 32 , 34 , 38 , and 39 may be considered suitable lead molecules to a drug candidate due to their LE , binding energies, and their affinity for the cellular targets CYP2C9 and xanthine oxidase.…”

“…In addition to displaying a best affinity for both proteins, the six molecules of the VPEO constituents have strong ligand binding to the protein, as shown by their low K d values. Regarding LE values, they are in the range of 0.47 and 0.51 kcal•mol −1 , compared to LE values greater than 0.3 kcal•mol −1 required to be considered as a reference [61].…”

Co-Prevalence of Virulence and Pathogenic Potential in Multiple Antibiotic Resistant Aeromonas spp. from Diseased Fishes with In Silico Insight on the Virulent Protein Network

“…Enzyme also provides stability to microorganisms to thrive under extremely adverse growth conditions. High-affinity inhibitors of the M4 protease family opened new therapeutic ways in clinical practice and computational biochemistry [62,63]. Nonapeptide, present in the aerolysin network, helps the toxin to depolarize the lipid bilayer permeability of the host cells with its calcium-binding domain and supports pore formation [64].…”