Analysis On The Promiscuity Of The Ligands

Ligand promiscuity attracts wide attention, which may be the consequence of many factors, such as the ligand’s flexibility or physical properties. Analysis on the causes of promiscuity will provide valuable guidance for drug design, especially for drug repurposing and multi-target medicine design. This thesis mainly studies the change of the ligand’s conformational and the protein pocket shape when a ligand binds to different proteins.4924ligands were extracted from sc-PDB database and the structures were preprocessed with the "standardize molecule" component in Pipeline Pilot. The ligand-protein complex structures were downloaded from PDB. For ligands which can bind to multiple proteins, the relationship between their physicochemical properties and the number or type of the binding proteins were analyzed. The conformational change of a ligand was evaluated with RMSD value, and, the shape change among the protein pockets that bound with a same ligand was measured with the similarity score by APOC program package. The results are as follows:1) The number of proteins which a ligand can bind to follows the power-law distribution. With increasing of the free-ID number, the AlogP of ligand decreases. And, with the increasing of the class number of the proteins, the hydrogen bond acceptor number, hydrogen bond donor number, and molecular polar surface area of the ligand increases.2) The RMSD values between different conformations of the same ligand experience an raising trend as the number of types(Family、Superfamily、Fold、Class) of the binding proteins increases. For most of these ligands, the maximum of the RMSD values are greater than2A, showing the ligand conformation changes greatly.3) The analysis of ligand RMSD value, protein pocket similarity and protein chain similarity indicated that ligand RMSD value is negatively correlated with the latter two. This shows that the change of ligand conformations is in agreement with that of protein pockets. Finally, we compared ligand RMSD value with protein pocket RMSD value, and found that the change of the protein pocket is greater than that of the ligand.