Phthalide derivatives as dihydrofolate reductase inhibitors for malaria: molecular docking and molecular dynamics studies

• Published in: Journal of biomolecular structure & dynamics Vol. 41; no. 11; pp. 5127 - 5137
• Main Authors: Ibraheem, Walaa, Makki, Alaa A., Alzain, Abdulrahim Altoam
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 24.07.2023
• Subjects: dihydrofolate reductase; docking; Folic Acid Antagonists - pharmacology; Humans; Malaria; Malaria - drug therapy; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; phthalide derivatives; Plasmodium falciparum; Tetrahydrofolate Dehydrogenase - chemistry; docking; phthalide derivatives; Malaria; molecular dynamics; dihydrofolate reductase
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2022.2080114

Plasmodium falciparum dihydrofolate reductase enzyme (P. falciparum DHFR) is one of the vital drug targets for malaria treatment, as this protein is indispensable for nucleotide metabolic pathways. This research aimed to discover promising phthalide derivatives against both wild and mutant P. falciparum DHFR enzymes through various computational techniques. The binding affinities were investigated using molecular docking, which showed five compounds having the highest affinity scores against both enzymes compared to the reference compounds. MM-GBSA calculations displayed favourable free binding energy. Moreover, the ADMET properties of the compounds are within acceptable ranges. The stability of the ligand-protein complexes was studied by Molecular Dynamics (MD) simulations. Depending on the results obtained from this research, we propose three compounds to be hit against P. falciparum DHFR activity which could be examined experimentally. Communicated by Ramaswamy Sarma