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Chalcone‐Quinoline Conjugates as Potential T. cruzi Cruzipain Inhibitors: Docking Studies, Molecular Dynamics and Evaluation of Drug‐Likeness
Author(s) -
Yepes Andrés F.,
QuinteroSaumeth Jorge,
CardonaG Wilson
Publication year - 2020
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202000777
Subject(s) - docking (animal) , stereochemistry , chemistry , chalcone , quinoline , in silico , molecular dynamics , protein data bank (rcsb pdb) , active site , combinatorial chemistry , biochemistry , computational chemistry , enzyme , organic chemistry , gene , medicine , nursing
We reported in a previous work the synthetic route of a novel series of conjugates based on chalcone‐quinoline, some of them were active against T. cruzi , even more active than the clinical drug benznidazole. Those results motivated us to pursue further computational studies. Thus, molecular docking was used to determine the in‐silico inhibition effects for the compounds against cruzipain (PDB:3IUT), an important druggable target for antiparasitic diseases. Notably, the docking results showed that the most experimental active compounds within two series, 1 a – f and 2 a – f , namely ( E )‐1‐(3,4‐dimethoxyphenyl)‐3‐(4‐((9‐(quinolin‐8‐yloxy)nonyl)oxy)phenyl)prop‐2‐en‐1‐one ( 1 e ) and ( E )‐3‐(furan‐2‐yl)‐1‐(4‐((5‐(quinolin‐8‐yloxy)pentyl)oxy)phenyl)prop‐2‐en‐1‐one ( 2 c ), also have the highest docking score (−7.3 and −7.4 kcal mol −1 , respectively). The good correlation between docking and the experimental data profile lead us to propose inhibition of cruzipain as the potential mechanism of action for the novel conjugates. By combining molecular dynamics with MM/PBSA methods, the stability and rationality of molecular docking studies were validated, and drug‐likeness studies showed suitable pharmacokinetics properties.