Insights from Molecular Docking and Experimental Studies for Antibacterial Therapy

In this study, a computer-aided drug design (CADD) approach was developed for a focused chemical library of eight synthesized thiazolo[5,4-c]isoquinoline (TzIQ) derivatives, including four neutral compounds and their corresponding cationic derivatives, all methylated at N4. Our CADD approach involved target prediction using Mondrian conformal prediction with the ChEMBL database, which contains data from 550 human protein targets with diverse bioactivity profiles. This analysis identified that TzIQ had a high probability of being active against the enzyme dihydrofolate reductase (DHFR). Moreover, molecular docking predictions against Staphylococcus aureus DHFR (saDHFR) and Escherichia coli DHFR (ecDHFR) highlighted three promising TzIQ for each enzyme: 2, 4, and 8 for saDHFR, and 4, 7, and 8 for ecDHFR. These compounds demonstrated significant ligand–protein energy scores and relevant binding affinities with the saDHFR and ecDHFR pocket residues, respectively. The subsequent in vitro antibacterial evaluation against S. aureus and E. coli confirmed the docking predictions for derivative 8 in both bacteria. Additionally, derivatives 6 and 7 emerged as novel antibacterial compounds against S. aureus, with all hits exhibiting MIC values ≤100 µg/mL.