Protein-small molecule docking with receptor flexibility in iMOLSDOCK.

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• The iMOLSDOCK technique was previously developed for induced-fit peptide-protein docking.
• Accurate protein-ligand docking is crucial for drug discovery and understanding biological interactions.

Purpose of the Study:

• To extend the iMOLSDOCK technique for docking nonpeptide small molecule ligands to receptor proteins.
• To benchmark and validate the performance of the extended iMOLSDOCK against established docking tools.

Main Methods:

• Utilized the mutually orthogonal Latin squares (MOLSs) technique to sample ligand and receptor flexibility.
• Extended iMOLSDOCK to accommodate nonpeptide small molecules in docking simulations.
• Validated the method using a dataset of 34 protein-ligand complexes and the Astex Diverse dataset.

Main Results:

• The extended iMOLSDOCK demonstrated superior performance compared to GOLD v5.2.1 and AutoDock Vina.
• The method achieved accurate prediction of optimal poses and conformations for nonpeptide ligands.
• Increased computational time was observed, indicating a trade-off between accuracy and speed.

Conclusions:

• The enhanced iMOLSDOCK is a powerful tool for flexible receptor docking of nonpeptide small molecules.
• This advancement in induced-fit docking can aid in rational drug design and lead optimization.
• The freely available MOLS 2.0 software facilitates broader application in the scientific community.