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

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