{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:09:18Z","timestamp":1791497358575,"version":"4.3.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p><jats:italic>Plasmodium falciparum<\/jats:italic> (<jats:italic>Pf<\/jats:italic>) 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 <jats:italic>Pf<\/jats:italic> 5-ALAS using pharmacophore modeling, virtual screening, qualitative structural assessment, <jats:italic>in silico<\/jats:italic> ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluation and molecular dynamics simulation. The best model of the tertiary structure of <jats:italic>Pf<\/jats:italic> 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 <jats:italic>Pf<\/jats:italic> 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 <jats:bold>CSMS00081585868<\/jats:bold> 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\u2019s active site amino acid residues. The <jats:italic>in silico<\/jats:italic> ADMET prediction showed that all ten best hits possessed relatively good pharmacokinetic properties. The qualitative structural assessment of the best hit, <jats:bold>CSMS00081585868<\/jats:bold>, 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 <jats:italic>Pf<\/jats:italic> 5-ALAS as confirmed from the RMSD obtained during the MD simulation.<\/jats:p>","DOI":"10.3389\/fmed.2022.1022429","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T05:39:58Z","timestamp":1673501998000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulation studies for identification of Plasmodium falciparum 5-aminolevulinate synthase inhibitors"],"prefix":"10.3389","volume":"9","author":[{"given":"Gbolahan 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