Template‐guided method for protein–ligand complex structure prediction: Application to CASP15 protein–ligand studies

Abstract

AbstractCritical Assessment of Structure Prediction 15 (CASP15) added a new category of ligand prediction to promote the development of protein/RNA‐ligand modeling methods, which have become important tools in modern drug discovery. A total of 22 targets were released, including 18 protein–ligand targets and 4 RNA‐ligand targets. We applied our recently developed template‐guided method to the protein–ligand complex structure predictions. The method combined a physicochemical, molecular docking method, and a bioinformatics‐based ligand similarity method. The Protein Data Bank was scanned for template structures containing the target protein, homologous proteins, or proteins sharing a similar fold with the target protein. The binding modes of the co‐bound ligands in the template structures were used to guide the complex structure prediction for the target. The CASP assessment results show that the overall performance of our method was ranked second when the top predicted model was considered for each target. Here, we analyzed our predictions in detail, and discussed the challenges including protein conformational changes, large and flexible ligands, and multiple diverse ligands in a binding pocket.