Workflow of DruGUI-2.0. (A) Uses PSF/PDB files with default probe set (isopropanol, isobutane, imidazole, benzene, acetamide, acetate, isopropylamine) to prepare druggability simulations for MDM2. (B) Solvated system with probes (sticks) and ions (spheres) ready for NAMD3 simulations. (C) Trajectory analysis identifies hot spots, probe binding preferences, and coordinating residues for pharmacophore modeling.
Druggability analysis of BCL-2 using DruGUI-2.0. Molecular dynamics simulations of BCL-2 (B-cell lymphoma 2) were performed in the presence of multiple probe molecules selected to mimic fragment-based NMR screening. DruGUI-2.0 identifies a highly druggable binding pocket with a predicted binding free energy of −14.5 kcal/mol, corresponding to the known inhibitor-binding site targeted by Venetoclax, which was originally discovered through fragment-based NMR screening.
Druggability analysis of the μ-opioid receptor in a membrane environment. The receptor is simulated embedded in a lipid bilayer and surrounded by probe molecules in explicit solvent. DruGUI-2.0 identifies two highly druggable sites, including a pocket overlapping the known morphine-binding site and a second site corresponding to the G-protein interaction interface, demonstrating its ability to detect both ligand-binding and protein–protein interaction sites in membrane proteins.
DruGUI-2.0 is a computational drug discovery tool for assessing the druggability of protein targets using molecular dynamics simulations in the presence of small probe molecules. By explicitly accounting for protein conformational flexibility, DruGUI-2.0 identifies druggable binding sites—including transient and allosteric pockets—that are often inaccessible to static structure-based approaches.
DruGUI-2.0 supports simulations in explicit solvent with an option to include membrane environments, enabling its application to both soluble proteins and membrane-embedded drug targets. The results provide quantitative insight into potential binding sites, probe preferences, and relative binding affinities, and can be used directly for pharmacophore modeling and virtual screening.
DruGUI-2.0 significantly extends the capabilities of the original DruGUI. While DruGUI was implemented as a standalone VMD plugin and limited to soluble proteins and a small probe set, DruGUI-2.0 is fully integrated into the ProDy API, enabling seamless combination with protein sequence, structure, and dynamics analyses.
The updated version introduces support for membrane proteins, modern force fields and simulation engines, and a vastly expanded probe library representing the chemical diversity of approved drugs. These improvements lead to more accurate identification of druggable sites, better correlation with experimental observations, and broader applicability to biologically and therapeutically relevant targets.
DruGUI-2.0 can be obtained from ProDy
Reference
Bakan A, Nevins N, Lakdawala AS, Bahar I
Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules
J Chem Theory Comput 2012 8(7):2435-2447.
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