Structure-based virtual screening, molecular docking and dynamics studies of natural product and classical inhibitors against human dihydrofolate reductase

Folate antagonists are classified as important and valuable therapeutic agents against infection, neoplastic, and inflammatory diseases. Dihydrofolate reductase (DHFR) is a biological target of two well-defined folate antagonists, classical and non-classical inhibitors. DHFR catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate benefits of NADPH as a cofactor. With the point to recognize new chemicals to be utilized for further structure-based drug design, a collection of 67753 molecules including chemicals and natural products have been screened through the docking method from the Zinc Database. The high ranked compound with regard to methotrexate (MTX), resulted to be three compounds comprises of ZINC29236925, ZINC31169388, and ZINC01629864, which further investigated by molecular dynamics (MD) simulation, Poisson–Boltzmann surface area method (MM-PBSA) and QMMM calculations. PCA analysis revealed that upon inhibitor binding, the DHFR folding is changed. Our QMMM data suggested that a structure with ZINC ID of ZINC31169388 has a stronger interaction with DHFR active site and could be a favorable candidacy for biological assessment and additional advanced improvement. Furthermore, ADMET prediction illustrated that all physicochemical factors of ZINC31169388 are within the satisfactory span described for human treatment.