RESUMEN
Leishmaniasis affects more than 12 million humans globally and a further 1 billion people are at risk in leishmaniasis endemic areas. The lack of a vaccine for leishmaniasis coupled with the limitations of existing anti-leishmanial therapies prompted this study. Cheminformatic techniques are widely used in screening large libraries of compounds, studying protein-ligand interactions, analysing pharmacokinetic properties, and designing new drug molecules with great speed, accuracy, and precision. This study was undertaken to evaluate the anti-leishmanial potential of some organoselenium compounds by quantitative structure-activity relationship (QSAR) modeling, molecular docking, pharmacokinetic analysis, and molecular dynamic (MD) simulation. The built QSAR model was validated (R2train = 0.8646, R2test = 0.8864, Q2 = 0.5773) and the predicted inhibitory activity (pIC50) values of the newly designed compounds were higher than that of the template (Compound 6). The new analogues (6a, 6b, and 6c) showed good binding interactions with the target protein (Pyridoxal kinase, PdxK) while also presenting excellent drug-likeness and pharmacokinetic profiles. The results of density functional theory, MD simulation, and molecular mechanics generalized Born surface area (MM/GBSA) analyses suggest the favourability and stability of protein-ligand interactions of the new analogues with PdxK, comparing favourably well with the reference drug (Pentamidine). Conclusively, the newly designed compounds could be synthesized and tested experimentally as potential anti-leishmanial drug molecules.Communicated by Ramaswamy H. Sarma.
RESUMEN
Leishmaniasis is one of the tropical diseases which affects over 12 million people mainly in the tropical regions of the world and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, as well as limitations of existing therapies necessitated this study which was focused on a combined virtual docking screening and 3-D QSAR modeling approach to design some diarylidene cyclohexanone analogs, while also performing pharmacokinetic analysis and Molecular Dynamic (MD) simulation to ascertain their drug-ability. As a result, the built 3-D QSAR model was found to satisfy the requirement of a good model with R2 = 0.9777, SDEC = 0.0593, F-test = 105.028, and Q2 LOO = 0.6592. The template (compound 9, MolDock score = - 161.064) and all seven newly designed analogs were found to possess higher docking scores than the reference drug (Pentamidine, Moldock score = - 137.827). The results of the pharmacokinetic analysis suggest 9 and the new molecules (9a, b, c, e, and f) as orally bioavailable with good ADME and safe toxicological profiles. These molecules also showed good binding interactions with the receptor (pyridoxal kinase). Additionally, the MD simulation result confirmed the stability of the tested protein-ligand complexes, with an estimated ∆G binding (MM/GBSA) of - 65.2177 kcal/mol and - 58.433 kcal/mol for 9_6K91 and 9a_6K91 respectively. Hence, the new compounds, especially 9a could be considered potential anti-leishmanial inhibitors.
RESUMEN
Lymphatic filariasis and onchocerciasis are common filarial diseases caused by filarial worms, which co-habit symbiotically with the Wolbachia organism. One good treatment method seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening and 3-D QSAR modeling were conducted on a series of Fifty-two (52) pyrazolopyrimidine derivatives against four Wolbachia receptors, including a pharmacokinetics study and Molecular Dynamic (MD) investigation, to find a more potent anti-filarial drug. The DFT approach (B3LYP with 6-31G** option) was used for the structural optimization. Five ligand-protein interaction pairs with the highest binding affinities were identified in the order; 23_7ESX (-10.2 kcal/mol) > 14_6EEZ (- 9.0) > 29_3F4R (- 8.0) > 26_6W9O (- 7.7) ≈ doxycycline_7ESX (- 7.7), with good pharmacological interaction profiles. The built 3-D QSAR model satisfied the requirement of a good model with R2 = 0.9425, Q2 LOO = 0.5019, SDEC = 0.1446, and F test = 98.282. The selected molecules (14, 23, 26, and 29) perfectly obeyed Lipinski's RO5 for oral bio-availability, and showed excellent ADMET properties, except 14 with positive AMES toxicity. The result of the MD simulation showed the great stability associated with the binding of 23 onto 7ESX's binding pocket with an estimated binding free energy (MM/GBSA) of - 60.6552 kcal/mol. Therefore, 23 could be recommended as a potential anti-filarial drug molecule, and/or template for the design of more prominent inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-022-00136-y.
RESUMEN
Lymphatic filariasis and onchocerciasis are two common filarial diseases caused by a group of parasitic nematodes called filarial worms, which play host to the bacteria organism Wolbachia. One good treatment approach seeks Wolbachia as drug target. Here, a QSAR study was conducted to investigate the anti-wolbachia activities (pEC50) of 52 pyrazolopyrimidine analogues, while using the built model to predict the pEC50 values of the newly designed analogues. Density Functional Theory was used for the structural optimization, while the model building was based on Genetic Function Algorithm approach. The built QSAR model was validated thus: R2 = 0.8104, R2 adj = 0.7629, Q2 cv = 0.6981, R2 test = 0.7501 and cRp2 = 0.7476. The predicted pEC50 of all newly designed compounds were higher than that of the template (43). The new compounds were; observed to pass the drug-likeness criteria, uniformly distributed to the brain, and found to be non-mutagenic. Also, the new compounds and the reference drug (doxycycline), were docked onto Ovarian Tumor (OTU) deubiquitinase receptor (PDB ID: 6W9O) using iGEMDOCK tool. This protein is known to help Wolbachia subvert host ubiquitin signaling. The resulting binding scores of the newly designed compounds except A5 were higher than that of doxycycline, while the protein-ligand interactions were majorly characterized by Hydrogen-bonding and hydrophobic interaction types. Therefore, the newly designed molecules could be developed as potential drug candidates for the treatment of lymphatic filariasis and onchocerciasis.
RESUMEN
The increasing problem of multi-drug resistant-tuberculosis has focused attention on developing new drugs that are not only active against drug-resistant tuberculosis, but also shorten the lengthy therapy. Therefore, this work employs the application of modeling technique to predict the inhibition activities of some prominent compounds which been reported to be efficient against Mycobacterium tuberculosis. To accomplish the purpose of this work, multiple regression and genetic function approximation were adopted to create the model. The established model was swayed with topological descriptors; MATS7s, SpMin4_Bhv, TDB3v and RDF70v. More also, interactions between the compounds and the target protein 'DNA gyrase' were evaluated via molecular docking approach utilizing the PyRx and discovery studio simulation software. Based on the docking analysis, compound 20 has the most noticeable binding affinity of -16.5 kcal/mol. Therefore, compound 20 served as a reference structural template and insight to design fourteen novel hypothetical agents with more prominent anti-tubercular activities. More also, compound 20j was observed with the highest activity among the designed compounds with a prominent binding affinity of -24.3 kcal/mol. Therefore, this research recommends in-vivo, in-vitro screening and pharmacokinetic properties to be carried out in order to determine the toxicity of the designed compounds.Communicated by Ramaswamy H. Sarma.