Quinoline-based Aromatic Aldehydes as Novel Inhibitors of Plasmodium falciparum Transketolase: An In-silico Study
Adesina, Adedamola Onikepo *
Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
Ayobami Damilare Adisa
Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
Fakuade, Ayodeji
Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
Abejide, Oluwamuyitomiwa Micheal
Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria.
*Author to whom correspondence should be addressed.
Abstract
Background: The emergence of drug-resistant Plasmodium falciparum strains, especially those showing resistance to artemisinin-based combination therapies (ACTs), highlights the critical need for new antimalarial compounds that target different biochemical pathways.
Objectives: This study explores the inhibitory potential of quinoline-derived aromatic aldehydes against Plasmodium falciparum transketolase, a key enzyme in the pentose phosphate pathway that plays a vital role in parasite nucleotide synthesis and redox homeostasis, through an in-silico assessment.
Methodology: A combination of ligand-based and structure-based drug design strategies was employed. Drug-likeness, pharmacokinetic and toxicological properties were assessed using qualitative drug estimation and ADMET profiling. Molecular docking was used to determine binding affinities, while binding free energies were calculated using molecular mechanics. The stability of binding interactions was further examined using molecular dynamics simulations.
Results: Molecular docking studies identified 3,4,5-trimethoxybenzaldehyde (A3) and 2-nitrobenzaldehyde (A6) as having the highest binding affinities for Plasmodium falciparum transketolase (−8.3 kcal/mol and −8.2 kcal/mol, respectively), outperforming the reference drug oxythiamine. MM-PBSA analysis further confirmed Compound A6 as the thermodynamically most favourable complex, exhibiting superior overall binding free energy (ΔG_bind), driven by significant van der Waals and covalent contributions. Pharmacokinetic evaluations, including drug-likeness and ADMET profiling, indicated favourable drug-like properties and low toxicity across all compounds. Molecular dynamics simulations over 100 ns further validated Compounds A3 (7-(3,4,5-trimethoxyphenyl) chromenoquinoline) and A6 (7-(2-nitrophenyl) chromenoquinolinone) as the most stable complexes with Plasmodium falciparum transketolase, recording average RMSD values of 0.24–0.25 nm, RMSF values of 0.12–0.14 nm, radii of gyration of 2.85–2.93 nm, and consistent hydrogen-bond persistence throughout the trajectory.
Conclusion: Compared with the reference drug oxythiamine, both compounds demonstrated superior conformational stability and active-site complementarity, reinforcing their potential as credible antimalarial lead candidates.
Keywords: Antimalarial resistance, Plasmodium falciparum transketolase, oxythiamine, Chromenoquinoline, ligand-based drug design, structure-based drug design