Screening of indole derivatives as the potent anticancer agents on dihydrofolate reductase: pharmaco-informatics and molecular dynamics simulation

Abstract Dihydrofolate reductase (DHFR) is a ubiquitous cellular enzyme involved in the biosynthesis of nucleotide and protein precursors, thus, the inhibition of human DHFR can be a promising strategy in cancer treatment. The design of effective anticancer drugs is an urgent need today according to the high spread of cancer. The indole molecule with diverse mechanisms of action and anticancer properties is one of the efficient pharmacophores in drug design. Hence, a virtual library of indole derivatives as a scaffold was selected for designing safer and more effective anticancer drugs against DHFR in this work. All indole derivatives utilized in the library design were selected regarding appreciable tumor growth inhibition. Structure–activity relationship (SAR), docking energy, ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, and effective non-covalent interactions were used to identify potential anticancer with indole scaffold. Results showed a higher number of indole moieties provide a strong attachment to the DHFR binding pocket and therefore more effective anticancer activity. The indole scaffold in combination with dichlorobenzene improves DHFR inhibition whereas barbituric acid weakens inhibition activity. In the following to validate the docking results, Molecular dynamics (MD) simulation and molecular mechanics generalized-Born surface area (MM-GBSA) indicated the permanent stability of the selected ligands into the DHFR binding pocket and the key amino acids. Therefore, promising pharmacophores based on indole-DHFR interactions were discovered, and the outcome could be useful in guiding future in vitro and in vivo drug discovery in cancer medicine. Communicated by Ramaswamy H. Sarma