Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library

Abstract

Cancer is characterized by altered cellular metabolism,and metabolicenzymes are considered as a promising target for anticancer therapy.Pyrimidine metabolism dysregulation is associated with various typesof cancer, particularly lung cancer, which is one of the leading causesof cancer-related mortality worldwide. Recent studies have shown thatsmall-cell lung cancer cells are particularly reliant on the pyrimidinebiosynthesis pathway and are sensitive to its disruption. DHODH, therate-limiting enzyme of the de novo pyrimidine production pathway,is essential in the production of RNA and DNA and is overexpressedin malignancies such as AML, skin cancer, breast cancer, and lungcancer, thereby highlighting DHODH as a viable target for developingdrugs to combat lung cancer. Herein, rational drug design and computationaltechniques were used to discover novel DHODH inhibitors. A small combinatoriallibrary was generated, and the top hits were synthesized and testedfor anticancer activity against three lung cancer cell lines. Amongthe tested compounds, compound 5c possessed a strongercytotoxicity (TC50 of 11 mu M) compared to the standardFDA-approved drug (Regorafenib, TC50 of 13 mu M) onthe A549 cell line. Furthermore, compound 5c demonstratedpotent inhibitory activity against hDHODH at a nanomolar level of421 nM. DFT, molecular docking, molecular dynamic simulations, andfree energy calculations were also carried out to understand the inhibitorymechanisms of the synthesized scaffolds. These in silico studies identifiedkey mechanisms and structural features that will be crucial for futurestudies.