Structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulation studies for identification of Plasmodium falciparum 5-aminolevulinate synthase inhibitors

Abstract

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.

Synthesis, in silico and in vitro antimicrobial efficacy of substituted arylidene-based quinazolin-4(3H)-one motifs

“…Unfavorable bond interactions were also observed, suggesting repulsive forces between molecules ( Tallei et al, 2021 ). All these interactions play major roles in the strength of protein–ligand complexes and in the docking scores obtained for each of the best hits ( Thillainayagam et al, 2017 ; Oduselu et al, 2023 ). Compound 3g formed a conventional hydrogen bond with ARG A213 of S. mutans sortase A (PDB ID: 4TQX) via the carbonyl oxygen on the quinazolinone core structure.…”

“…Figures 3A,B show RMSD plots of the c-alpha of the protein backbones and of the compounds in the protein–ligand complex. Significant changes, with fluctuations in RMSD by > 3, suggest instability of the ligand or the protein in the complex ( Oduselu et al, 2023 ). The MD simulation revealed that all the protein targets for the predicted antibacterial activities had fluctuations of RMSD by < 3, except in the case of 4TQX when complexed with compound 3 g ( Figure 3A ).…”

Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) of Plasmodium falciparum

“…The toxicity risk can, however, be removed by hit-to-lead optimization, this is because toxicity is caused by the presence of a high-risk fragment/pharmacophore in the compound. 35 This study is, however, limited by the fact that little is known about the Pf PTPS enzyme and that known inhibitors have not yet been identified for this enzyme, especially in Plasmodium parasites.…”

In silico studies of benzimidazole derivatives as sustainable inhibitors against Methicillin-resistant Staphylococcus aureus

“…The prepared ligands and known antibiotics (gentamicin, penicillin G, streptomycin, ampicillin) were screened against PBP2A using Autodock vina [21]. The active site for the main and allosteric sites was set using the amino acid residues identified by [22].…”