డ్రగ్ డిజైనింగ్: ఓపెన్ యాక్సెస్
అందరికి ప్రవేశం

నైరూప్య

Plasmodium falciparum Histo-Aspartic Protease (HAP) inhibitor: Toxicity Investigation and Docking Study of 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde derivatives

Aina S Oluwafemi, Adams A Luqman, Bello J Adebayo, Familoni B Oluwole*

Background: Aspartic proteases possess catalytic sites for the hydrolysis of peptide bonds, which makes them potential drug targets in malaria parasites. Inhibiting Histo-Aspartic Protease (HAP), Aspartate (Asp215) and Histidine (His32) residues of P. falciparum disrupt the growth phase and ability to catalyze erythrocyte hemoglobin degradation.

Objectives: To synthesize compound 2-(2-benzoyl-4-methyl phenoxy) quinoline-3-carbaldehyde, through sp² C-H activation protocols. To carry out in silico screening of fifty hypothetical compounds for their toxicity, pharmacokinetics, bioactivity score and binding affinities using Protox II web server, to carry out virtual screening of their toxicity and compliance with all drug-likeness rules. To carry out a molecular docking study of the docking of the ligands and ten references antimalarial drugs against HAP.

Methods: 2-(2-Benzoyl-4-methylphenoxy) quinoline-3-carbaldehyde was synthesized. In silico screening using Protox II webserver and molecular docking of the ligands and ten reference antimalarial drugs against HAP were carried out using ADME predictions and PyRx 0.8 AutoDock Vina Wizard.

Results: Nine lead compounds showed no toxicity to human cells. The lead compounds were generally highly or moderately bioactive for six bioactivity score parameters. Compound A31 was the best reference drug. While compound A31 and mefloquine both showed no interactions with either Asp215 or His32 in the binding pockets, compound A5 showed π-π stacking interactions. There was a significant hydrophobic interaction to suggest good water-lipid cell membrane transport within the Pf HAP protein, while the quinoline core exposure to a large solvent accessibility surface predisposes it to a more open conformation and binding interaction with the reactive site target residues.

Conclusion: Based on the other drug-likeness parameters investigated, compound A5, 2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde, can be recommended as a possible candidate for new antimalarial drug development in line with SDG goal 3 on health and well-being.