Targeting Glycine N-Methyltransferase: A Computational Pipeline for Novel Anti-Pancreatic Cancer Leads

Glycine N-Methyltransferase (GNMT) has emerged as a potential drug target due to its pivotal role in pancreatic cancer development. This study utilized an integrated computational pipeline to identify promising novel GNMT inhibitors. The study was initiated by selecting overexpressed genes from microarray datasets, from which the five most overexpressed genes across the datasets were identified for further analysis: Albumin, Aquaporin 8, TMED6, Tex11 and GNMT. Three structurally diverse compound libraries, the FDA-approved ASINEX anticancer library, the comprehensive marine natural products database (CMNPD) and the Cambridge library, underwent extensive structure-based virtual screening via a molecular docking protocol, resulting in the selection of the top nine lead compounds, three from each library. The compounds are ASINEX — AAM_10789997, AEM_12453662 and ASN-12712084, while CMNPD — CMNPD4126, CMNPD4356 and CMNPD4327 and Cambridge — RAPAMYCIN, EVEROLIMUS and AZD2281. Their binding affinities were below −8 kcal/mol, suggesting stronger interaction and stability of GNMT-ligand complexes. Density Functional Theory (DFT) results have shown the stability and reactivity of these compounds. The selected lead compounds demonstrated a favorable pharmacokinetic profile, fulfilling the Lipinski Rule 5 criteria. Furthermore, the study was proceeded with molecular dynamics (MD) simulation of 100 ns to identify the interaction of GMNT-ligands under a dynamic environment. The RMSD of all compounds ranged from 2.61 to 3.95 Å. The post-simulation analysis, conducted with the aim of gaining a deeper insight into protein–ligand complexes, included principal component analysis (PCA), hydrogen bonding studies, secondary structure studies and salt bridge analysis. Furthermore, MMPB/GBSA calculations and entropy energy estimations were carried out for the validation of the energetic favorability of the selected leads. The study identified nine lead compounds with stronger interaction, structural stability and a promising pharmacokinetics profile, highlighting their potential as lead compounds for further development. Nevertheless, additional wet lab investigations are necessary to evaluate these drugs’ potential to combat cancer.