Structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulation studies for...

Plasmodium falciparum (Pf) 5-aminolevulinic acid synthase (5-ALAS) is an essential enzyme with high selectivity during liver stage development, signifying its potential as a prophylactic antimalarial drug target. The aim of this study was to identify important potential lead compounds which can serve as inhibitors of Pf 5-ALAS using pharmacophore modeling, virtual screening, qualitative structural assessment, in silico ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluation and molecular dynamics simulation. The best model of the tertiary structure of Pf 5-ALAS was obtained using MolProbity, while the following databases were explored for the pharmacophore-based virtual screening: CHEMBL, ChemDiv, ChemSpace, MCULE, MCULE-ULTIMATE, MolPort, NCI Open Chemical Repository, LabNetwork and ZINC databases. 2,621 compounds were screened against the modeled Pf 5-ALAS using AutoDock vina. The post-screening analysis was carried out using Discovery Studio while molecular dynamics simulation was performed on the best hits using NAMD-VMD and Galaxy Europe platform. Compound CSMS00081585868 was observed as the best hit with a binding affinity of -9.9 kcal/mol and predicted Ki of 52.10 nM, engaging in seven hydrogen bonds with the target's active site amino acid residues. The in silico ADMET prediction showed that all ten best hits possessed relatively good pharmacokinetic properties. The qualitative structural assessment of the best hit, CSMS00081585868, revealed that the presence of two pyridine scaffolds bearing hydroxy and fluorine groups linked by a pyrrolidine scaffold contributed significantly to its ability to have a strong binding affinity with the receptor. The best hit also showed stability in the active site of Pf 5-ALAS as confirmed from the RMSD obtained during the MD simulation.