In Silico Study Probes Potential Inhibitors of Human Dihydrofolate Reductase for Cancer Therapeutics

Abstract

Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes thereduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of humanDHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cellproliferation. In the current study, ligand-based pharmacophore modeling identified and evaluatedthe critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generatedfrom known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS)deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features,including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and onehydrophobic (HYP). Hypo1 was validated using Fischer's randomization, test set, and decoy setvalidations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex,National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered byan absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test andLipinski's rule of five, where the drug-like hit compounds were identified. The hit compounds weredocked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67(docking score for the reference compound), clustering analysis, and hydrogen bond interactionswere identified. Furthermore, molecular dynamics (MD) simulation identified three compounds asthe best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogenbond interactions with hDHFR, and low binding free energy (−127 kJ/mol to −178 kJ/mol). Finally,the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFRin human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoidarthritis chemotherapeutics.

Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents

“…Each resin-bound intermediate ( IV ) was washed before proceeding to the next stage. In the last stage of the process, the resins were dried and treated with TFA/DCM (50:50) [ 42 ]. After evaporation of the solvents, we yielded the products 1–18 as glaze solids.…”

“…There is a significant number of molecular modelling studies concerning h DHFR inhibition as well as plenty of high resolution crystal structures of enzyme-inhibitor complexes [ 38 , 39 , 41 , 42 ]. This provides a solid foundation for structure-based design studies of potent h DHFR inhibitors.…”

“…This provides a solid foundation for structure-based design studies of potent h DHFR inhibitors. It is believed that the most relevant residues in the ligand binding to the h DHFR are Ile-7, Glu-30, Phe-31, Phe-34, Leu-67, Arg-70, and Val-115 [ 38 , 41 , 42 ]. These residues were also found to be important in our previous study [ 43 ].…”

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

“…It is believed that the most important residues involved in the DHFR inhibition activity are Ile-7, Glu-30, Phe-34, and Val-115 [52,53]. This is reflected in the high binding energy of MTX, which exhibits interactions with these residues.…”

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

“…Potential inhibitors of hDHFR (109-111) ( Fig. 10), were identified recently by Rana et al [189] using 3D-QSAR pharmacophore modeling. 3D-QSAR pharmacophore modeling has become an increasingly acceptable approach for probing novel lead candidates in computational drug designing as fundamental platforms to develop effective chemotherapeutics in cancer and rheumatoid medications [189].…”