article · Future Journal of Pharmaceutical Sciences
Computational screening and molecular docking were conducted on sixteen designed aryl amine-based triazolopyrimidine derivatives targeting the Plasmodium falciparum dihydroorotate dehydrogenase enzyme. Molecular docking simulations revealed that compound D16 displayed the strongest binding affinity and stability, characterised by a re-rank score of minus 114.205 kcal/mol, facilitated by hydrophobic contacts and a hydrogen bond with the active LEU359 residue. Predictive pharmacokinetic profiling demonstrated that all sixteen compounds adhered strictly to Lipinski rule of five benchmarks, confirming their general drug-likeness. In addition, the evaluated derivatives displayed favourable characteristics regarding molar refractivity, rotatable bond counts, skin permeability, and blood-brain barrier penetration. These computational findings offer structural insights that may assist in the rational design and optimisation of new antimalarial agents.
Malaria continues to cause significant morbidity and mortality, making the discovery of new therapies essential. Using computational modeling to identify how novel chemical compounds bind to critical parasite enzymes helps researchers select the most promising candidates early. This approach reduces the time and expense needed to identify potential drug leads before progressing to expensive laboratory synthesis and biological testing.
This research represents early-stage, computational discovery and remains far from clinical or commercial deployment. The identified molecular structures may be of interest to academic drug discovery groups and pharmaceutical research teams seeking novel scaffolds targeting malaria. Substantial laboratory work, including chemical synthesis, enzymatic assays, cellular testing, and preclinical safety evaluations, is required before these compounds could advance toward potential therapeutic development.
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Abstract Background The sixteen (16) designed data set of substituted aryl amine-based triazolopyrimidine were docked against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) employing Molegro Virtual Docker (MVD) software and their pharmacokinetic property determined through SwissADME predictor. Results The docking studies shows compound D16, 5-((6-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)benzo[b]thiophen-4-ol to be the most interactive and stable derivative (re-rank score = − 114.205 kcal/mol) resulting from the hydrophobic as well as hydrogen interactions. The hydrogen interaction produced one hydrogen bond with the active residues LEU359 (H∙∙H∙∙O) at a bond distances of 2.2874 Å. All the designed derivatives were found to pass the Lipinski rule of five tests, supporting the drug-likeliness of the designed compounds. Conclusion The ADME analysis revealed a perfect concurrence with the Lipinski Ro5, where the derivatives were found to possess good pharmacokinetic properties such as molar refractivity (MR), number of rotatable bonds (nRotb), log of skin permeability (log Kp), blood-brain barrier (BBB). These results could a deciding factor for the optimization of novel antimalarial compounds.
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DOI: 10.1186/s43094-021-00288-2
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