InSilico structure based designing of dihydrofolate reductase enzyme antagonists and potential small molecules that target DHFR protein to inhibit the folic acid biosynthetic pathways

Abstract

Cancer has several pathways by which it is developed in our body. Among them folic acid biosynthetic pathway is one where dihydrofolate reductase (DHFR) enzyme converts dihydrofolate into tetrahydrofolate which leads to unwanted and uncontrollable growth of tissues. Our aim of this study is to design DHFR antagonistic potential small molecules that inhibits Folic Acid Biosynthetic Pathways. In this study, Human DHFR obtained from Protein Data Bank (PDB) were docked with several established anticancer drugs including Afatinib, Doxorubicin, Trimetrexate, Curcumin & Trimethoprim and several potential small molecules including Acarbose, Adenosine monophosphate, Abacavir, Aceprometazine & Isoxyl; obtained from PubChem and Drug Bank respectively. PyMOL and PyRx were used to visualize, curate and dock. For validation purpose Discovery Studio and Ramachandran Plot were run. Results after docking showed best binding affinities of established anticancer drugs with Human DHFR throughout the generations for example Methotrexate to Trimethoprim. Potential small molecules which belong from different therapeutic classes.