FragPELE

FragPELE performs fragment-based growth from bound cores and protein–ligand conformational sampling to support hit-to-lead optimization by predicting induced-fit adaptations and cryptic sub-pockets.

Key Features:

• Fragment Growth from Bound Cores: FragPELE grows fragments from bound cores to explore protein–ligand conformational space.
• Induced-Fit Simulation: FragPELE simulates protein conformational adaptation upon ligand binding to predict cryptic sub-pockets that may open due to specific R-groups.
• Crystallographic Prediction: FragPELE can reproduce and predict crystallographic ligand binding modes, including scenarios with hidden binding sites.
• Ranking and Comparative Performance: FragPELE ranks ligand activities and has been evaluated against FEP+, SP, Induced-Fit Glide, and MMGBSA simulations for cavity discovery and ligand ranking.

Scientific Applications:

• Hit-to-Lead Optimization: FragPELE supports optimization of initial chemical hits to improve binding affinity through fragment growth and induced-fit modeling.
• Identification of Cryptic Binding Sites: FragPELE identifies novel cavities and sub-pockets that emerge upon ligand modification or R-group changes.
• Ligand Ranking and Prioritization: FragPELE ranks ligand activities to prioritize candidate compounds for further validation.

Methodology:

FragPELE grows fragments from bound cores and simulates dynamic protein–ligand interactions to explore conformational changes upon binding and identify new binding sites.