In Silico Study of 17-DMAG Derivatives: Integrating QSAR, Molecular Docking, Molecular Dynamics, and ADME Analysis

The Hsp90 protein is crucial for cancer cell survival by regulating essential processes such as cell division, proteostasis, and the correct folding of proteins, including transcriptional factors, growth factors, and kinases. Due to its therapeutic relevance, Hsp90 has become a target for developing anticancer drugs. In this in silico study, a 2D-QSAR analysis was performed with geldanamycin derivatives, 33 of these selected for the training set, obtaining a model with predictive parameters (R² = 0.710, Q² = 0.626, F = 17.060). The test set of 10 compounds reached an external R² of 0.610. Additionally, a molecular docking between geldanamycin derivatives and Hsp90 was carried out using the AutoDock4.2 program; the best candidates were selected according to their binding energy and ligand efficacy to form complexes, and the interactions were analyzed. The protein-ligand complexes with the best binding energy were subjected to 100-ns molecular dynamics simulations to evaluate the stability of the complexes as a function of time, and the binding free energies were calculated for each complex. Finally, an ADME analysis was performed using SwissADME, allowing the design of new ligands with improved binding affinity and optimized pharmacokinetic properties compared to their predecessors for developing Hsp90 inhibitors.