Speaker
Description
Malaria, driven by drug-resistant Plasmodium falciparum, necessitates novel therapeutic targets. The parasite’s mitochondrial cytochrome bc1 (cyt bc1) complex, distinct from its human counterpart, is a validated target for selective inhibition. Quinolone derivatives from the medicinal plant Crinum firmifolium offer potential as novel inhibitors. This study investigated the inhibitory potential of eight quinolone derivatives (C1–C8) against the cyt bc1 complex using molecular docking, complemented by ADMET profiling and molecular dynamics (MD) simulations. Docking revealed binding energies ranging from –6.2 to –9.0 kcal/mol, with compounds C6 (–9.0 kcal/mol), C4 (–8.7 kcal/mol), C8 (–8.3 kcal/mol), and C3 (–8.4 kcal/mol) surpassing the natural substrate ubiquinol (–7.0 kcal/mol) and reference inhibitors antimycin A (–7.2 kcal/mol) and decoquinate (–7.9 kcal/mol). Notably, C6 exhibited binding affinity close to potent experimental inhibitors ELQ-300 (–10.0 kcal/mol) and GSK932121 (–10.4 kcal/mol), indicating strong potential to disrupt the parasite’s mitochondrial electron transport chain. ADMET predictions indicate favorable pharmacokinetics, good oral bioavailability, and low toxicity for the top candidates. MD simulations results suggest the stability of key protein–ligand complexes under physiological conditions. These results position C. firmifolium-derived quinolones, particularly C3, C5 and C6, as promising candidates for developing next-generation cyt bc1 inhibitors, warranting further biochemical and in vivo studies.
Keywords: Plasmodium falciparum, Quinolone derivatives, Mitochondrial electron transport chain, Drug resistance, Cytochrome bc1 complex