Abstract 4461: Utilizing steered molecular dynamics simulations for enhanced virtual screening: Active pharmacophore search by dynamic corrections to target MKK3-MYC interactions

Abstract The complex interplay between mitogen-activated protein kinase 3 (MKK3) and the MYC proto-oncogene protein is critical for cancer progression, especially in triple negative breast cancer (TNBC). Despite substantial advancements, effective MYC-targeted drug discovery remains a challenge, underscoring the need for innovative approaches to manage MYC-dependent malignancies. One promising strategy involves disrupting the protein-protein interactions (PPIs) between MKK3 and MYC, as MKK3-mediated activation of MYC is pivotal in multiple cell types, highlighting a new target for therapeutic interventions in MYC-driven cancers. In this study, we employed a novel in silico approach to screen small molecule libraries targeting the MKK3-MYC interaction. Dynamic structure-based pharmacophore models were created to screen these libraries, identifying compounds that effectively aligned with the specified pharmacophore features. Physics-based simulations were then conducted on the selected hits. Steered molecular dynamics (sMD) simulations were employed to evaluate the correlation between the force required to dissociate the candidate ligands from the binding pocket and their corresponding average binding free energies. Comparative analysis of the average binding free energies of these identified hits, relative to the reference compound SGI-1027, indicates that the selected molecules have promising predicted binding affinities. These findings may represent a significant step forward in our ability to modulate MYC activation for cancer therapy. Citation Format: Muhammet Eren Ulug, Saima Ikram, Ehsan Sayyah, Serdar DURDAGI. Utilizing steered molecular dynamics simulations for enhanced virtual screening: Active pharmacophore search by dynamic corrections to target MKK3-MYC interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4461.