Computational study of quinoline-based thiadiazole compounds as potential antileishmanial inhibitors

• Published in: New journal of chemistry Vol. 46; no. 36; pp. 17554 - 17576
• Main Authors: Khaldan, Ayoub, Bouamrane, Soukaina, El-mernissi, Reda, Alaqarbeh, Marwa, Hajji, Halima, Alsakhen, Nada, Maghat, Hamid, Ajana, Mohammed Aziz, Sbai, Abdelouahid, Bouachrine, Mohammed, Lakhlifi, Tahar
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 20.09.2022
• Subjects: Hydrogen bonds; Molecular docking; Molecular dynamics; Molecular structure; Parasitic diseases; Quinoline; Receptors; Thiadiazoles
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d2nj03253h

Leishmaniasis is a severe disease caused by protozoan parasites of the genus Leishmania and it is accountable for sizable morbidity and mortality worldwide. So far, no effective treatments for Leishmaniasis have been reported, and chemotherapy may be the only strategy for treating this disease. In this study, twenty quinoline-based thiadiazole compounds were examined, based on previous experimental studies. These molecules have been reported to have potent and selective antileishmanial activity. Using three-dimensional quantitative structure-activity relationships (3D-QSAR), sixteen molecules were used to generate CoMFA and CoMSIA/SEHD models with Q 2 values of 0.504 and 0.677, respectively, and R 2 values of 0.911 and 0.983, respectively. Also, promising potential was confirmed based on preliminary in silico ADMET predictions. Molecular docking studies confirmed the interaction modes between the quinoline-based thiadiazole molecules and the receptor, which showed that molecules Y1 and Y2 were stabilized at the active site of the target receptor through conventional hydrogen bonds with Ser14 (3.25 Å), Cys52 (3.78 Å), Thr335 (3.23 Å), Lys60 (3.11 Å), Cys52 (3.48 Å), Ser178 (2.94 Å), and Arg287 (3.21 Å) residues. Furthermore, molecular dynamics simulations for 100 ns via MM-GBSA evaluation showed promising results for molecules Y1 and Y2 . Therefore, the outcomes of this work encourage further experimental and scientific studies of compounds Y1 and Y2 , which could be antileishmanial agents with high inhibitory potency. Leishmaniasis is a severe disease caused by protozoan parasites of the genus Leishmania and it is accountable for sizable morbidity and mortality worldwide.