Discipline: Chemistry and Chemical Sciences
Subcategory: Cancer Research
Steven Ewell - Florida Agricultural and Mechanical University
Co-Author(s): Linda Williams, Florida A&M University, Tallahassee, FL; Clement Yadjou, Florida A&M University, Tallahassee, FL; Suresh Eyunni, Florida A&M University, Tallahassee, FL; Bereket Mochona, Florida A&M University, Tallahassee, FL.
Discoidin Domain Receptor (DDR1) is a receptor tyrosine kinase activated by triple-helical collagens and has been linked to several cancers and inflammatory conditions. Although there are some selective DDR1 inhibitors that have been discovered as anticancer agents during the last two decades, a combination of elevated cytotoxicity, poor metabolism, and pharmacokinetic profile has prevented more in-depth studies from being performed. As such, no DDR1 inhibitor has reached clinical investigation to date, forming an urgent need to develop specific DDR1 inhibitor(s) using Computer-Aided Drug Design (CADD) approaches. In this study, the interaction of DDR1(PDB:4CKR) with the recently developed ligand, VU6015929 was utilized to generate a six-point e-pharmacophore model for screening ZINC chemical database. The virtual screening for potential 4CKR inhibitors generated 952 hits. The hits were filtered and ranked using the high throughput virtual screening technique (HTVS), and the 10 top scoring compounds were subjected to molecular docking analysis. The molecular docking results displayed that all compounds adapted a similar binding mode and orientation within the active site of the 4CKR receptor. Compounds A, F, and G showed strong binding interactions in the active pockets of target proteins of 4CKR with the least binding energies. To get insight into the dynamic behavior and stability of the identified compounds in the active site of the 4CKR, a molecular dynamic (MD) simulation was conducted for 100 ns. The root-mean-square deviation (RMSD), the root means square fluctuation (RMSF), and the radius of gyration was computed for apo-protein (no ligand bound) and ligand-complexes. RMSD and RMSF were used to explain the stability of proteins and ligand. Compound F showed more promising results through docking and simulation analysis as compared to VU6015929. The ligand-receptor contacts, including hydrogen bonding, hydrophobic interactions, ionic and water bridges were presented through a histogram. Additionally, specific amino acids involved in the interactions were identified through a timeline histogram for every trajectory, and the in-silico results of the two techniques supported each other. Nevertheless, in vivo and in vitro studies are needed to remodel and establish solid experimental evidence of the three inhibitors.
Funder Acknowledgement(s): This research was also made possible by Grant Numbers U54CA233396, U54CA233444, & U54CA233465 from the National Institutes of Health (NIH), and National Cancer Institute (NCI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.
Faculty Advisor: Mochona, Bereket, email@example.com
Role: I used multiple computer softwares to study the chemical interactions between the protein-ligand complex of the protein of interest. Of the selected ligands for further study I studied and compared them to the original ligand, VU6015929, to evaluate there anti-cancer properties.