Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors

Abstract

The pharmacological inhibition of the bacterial collagenases (BC) enzymes is considered a promising strategy to block the virulence of the bacteria without targeting the selection mechanism leading to drug resistance. The chemical structures of the Clostridium perfringens collagenase A (ColA) inhibitors were analyzed using Bemis–Murcko skeletons, Murcko frameworks, the type of plain rings, and docking studies. The inhibitors were classified based on their structural architecture and various scoring methods were implemented to predict the probability of new compounds to inhibit ColA and other BC. The analyses indicated that all compounds contain at least one aromatic ring, which is often a nitrobenzene fragment. 2-Nitrobenzene based compounds are, on average, more potent BC inhibitors compared to those derived from 4-nitrobenzene. The molecular descriptors MDEO-11, AATS0s, ASP-0, and MAXDN were determined as filters to identify new BC inhibitors and highlighted the necessity for a compound to contain at least three primary oxygen atoms. The DrugBank database was virtually screened using the developed methods. A total of 100 compounds were identified as potential BC inhibitors, of which, 10 are human approved drugs. Benzthiazide, entacapone, and lodoxamide were chosen as the best candidates for in vitro testing based on their pharmaco-toxicological profile.

Ecotoxicological risk assessment of pesticides against different aquatic and terrestrial species: using mechanistic QSTR and iQSTTR modelling approaches to fill the toxicity data gap

“…The feature MDEO-11 indicates the molecular distance edge between all primary oxygens, 66 which is related to the molecular graph and considers only primary oxygen atoms bound to one non-hydrogen atom, regardless of the bond type. It represents the ratio of the number of primary oxygen atoms to the average graph distance between each pair of primary oxygen atoms, thus revealing molecular conformation and polarity, as can be seen in groups such as –NO 2 , –OH, SO 2 and >CO. 67 The more these feature groups, the greater the polarity, thus leading to a lower toxicity of the molecule. Chemicals with high MDEO-11 values were commonly less toxic, as evidenced by the low toxic compound 272 (Oryzalin, 19044-88-3) that had the maximum MDEO-11 value (3.11) in the modeling dataset (Fig.…”

Interaction of Some Asymmetrical Porphyrins with U937 Cell Membranes–In Vitro and In Silico Studies

“…Templates were selected manually, based on relevant experimentally determined conformations, such as human SERCA2b in E2 state (PDB ID: 6LN9 [ 37 ]), calcium-free human Slo1 in complex with auxiliary protein β4 (PDB ID: 6V35 [ 38 ]), and SUR2B subunit of rat K ATP in propeller-like conformation (PDB ID: 7MIT [ 39 ]). The qualities of the modeled structures were compared with structures retrieved from the AlphaFold database, and the most optimal models were retained for molecular docking studies [ 40 ]. Quality assessment was performed using the MolProbity 4.5.1 web-server [ 41 ].…”

The Polyphenolic Profile and Antioxidant Activity of Five Vegetal Extracts with Hepatoprotective Potential

“…The poses of redocked compounds were superposed on the initial conformation of the protein-ligand complexes to calculate the Root-Mean-Square Deviation (RMSD) values. The ligands used for validation also served as positive controls for docking score comparisons [102,103].…”