Molecular Regulator Driving Endometriosis Towards Endometrial Cancer: A Multi-Scale Computational Investigation to Repurpose Anti-Cancer drugs.

ABSTRACT

Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR_8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (-7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (-3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of -55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was -6.91 eV and lowest unoccupied molecular orbital was -3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment.