Identification and deciphering novel compounds dynamics against DTYMK: A potential oncogene against pancreatic cancer

Abstract

Deoxythymidylate kinase (DTYMK) plays a key role in the progression of pancreatic cancer (PC). The computational study began by selecting DTYMK as an anti-cancer target and using a drug library called the FDA-approved anticancer drug library, which contains 1745 compounds. Using molecular docking analysis, MD simulation, and pharmacokinetics profiling, the study identified three novel drug compounds, AZD2281, MDV3100, and carbamazepine with docking scores of −9.8 kcal/mol, −9.7 kcal/mol, and −9.6 kcal/mol, respectively. Additionally, the control compound (E)-1-(4-(hydroxy (phosphonooxy) phosphoryl) but-2-en-1-yl)-5-methyl pyrimidine-1, 3-diium-2, 4-bis (olate) showed a binding affinity of −7.3 kcal/mol. All three compounds met the Lipinski Rule of Five and were considered drug-like. The DTYMK complexes had mean RMSD values of 2.00 Å, 2.07 Å, 1.92 Å, and 2.84 Å for AZD2281, MDV3100, carbamazepine, and the control, respectively. The AZD2281 complex demonstrated the highest stability with no major deviation observed. Salt bridge analysis revealed key interactions such as Glu140-Arg14, Glu26-Arg22, Glu40-Arg37, and Asp103-Lys106. PCA analysis was performed to simplify large datasets, revealing that the eigenvalue patterns of the complexes were quite distinct. MMGB/PBSA calculations showed values of −95.96 kcal/mol and −97.36 kcal/mol for AZD2281, indicating its stability during ligand binding. The most suitable entropy value for AZD2281 suggested the most consistent and ordered binding. This in silico approach identified novel therapeutic compounds for pancreatic cancer, which still require experimental validation and may be modified for targeting DTYMK.