Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2.

A series of thiuram disulfides 1-6 which had been previously synthesized and characterized,[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.

Computational studies of the properties and activities of selected trisubstituted benzimidazoles as potential antitubercular drugs inhibiting MTB-FtsZ polymerization.

Trisubstituted benzimidazoles (trisbenz) are significantly active against nonreplicating Mycobacterium tuberculosis (MTB) by inhibiting the polymerization of Filamentous Temperature Sensitive Mutant Z (FtsZ), an essential bacteria cell division protein. In-depth in-silico study of 5 of the most active trisubstituted benzimidazoles; trisbenz 1, 2, 3, 4 and 5, giving insight into their properties, such as stability, bioavailability, interactions with residues at the binding site of MTB-FtsZ and their influence on structural dynamics of the protein have been conducted. This was achieved through the application of in-silico methods including density functional theory (DFT) calculations, ADME properties calculations, molecular docking and molecular dynamics simulations. A DFT approach was applied to predict reactivity properties of potent FtsZ inhibitors, and the results reveal the relative reactivity of these inhibitors as bioactive moieties. The estimated ADME properties predicted all 5 compounds to be bioavailable and suitable for oral administration. Molecular docking, binding free energy, RMSD, RMSF, and hydrogen bond analysis confirmed these 5 compounds as potent MTB-FtsZ inhibitors. Although analyses proved these compounds to be bioactive and potent MTB-FtsZ inhibitors, however, trisbenz 1 appeared to be the most active against this protein while trisbenz 5 was the least active. This study further confirms the experimental study while also giving insight on the compounds mechanism of action and presents their bioavailability properties.

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb-FtsZ polymerisation through ligand-based virtual screening and molecular dynamics simulations.

Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperature-sensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

Drug repurposing: Fusidic acid as a potential inhibitor of M. tuberculosis FtsZ polymerization - Insight from DFT calculations, molecular docking and molecular dynamics simulations.

Filamentous Temperature Sensitive Mutant Z (FtsZ), an important cell division protein in bacteria, has been validated as a potential target for antibiotics development. Citric acid has been found to inhibit the polymerization of Mycobacterium tuberculosis (MTB) FtsZ and several other drugs have been predicted as potential inhibitors through a gene ontology-based drug repurposing approach. An in-depth study on four of the predicted drugs; Fusidic acid (FusA), l-tryptophan, Carbamic acid, and 2-(3-guanidinophenyl)-3-mercaptopropanoic acid, as potential inhibitors of MTB-FtsZ polymerization was conducted using Citric acid as reference compound. The applied in silico methods involve DFT calculations, molecular docking and molecular dynamics simulations. DFT approach was applied to evaluate selectivity and stability properties of the predicted drugs. Calculated parameters including non-linear optical properties, charge distribution and electrostatic potential analyses enabled selectivity prediction of these potential drugs. DFT-based descriptors revealed FusA as the most potent compound, even more reactive than the referenced compound, Citric acid, which is also supported from the molecular docking study. Parameters including MM/PBSA binding free energies, RMSD, RMSF, RoG and hydrogen bond analysis also support FusA as the best potential MTB-FtsZ polymerization inhibitor, that forms a stable complex with the protein and impose greatest level of rigidity to the protein.