title: Promiscuity and the conformational rearrangement of drug-like molecules: insight from the protein data bank.
abstract: Selectivity is a central aspect of lead optimization in the drug discovery process. Medicinal chemists often try to decrease molecular flexibility to improve selectivity, given the common belief that the two are interdependent. To investigate the relationship between polypharmacology and conformational flexibility, we mined the Protein Data Bank and constructed a dataset of pharmaceutically relevant ligands that crystallized in more than one protein target while binding to each co-crystallized receptor with similar in vitro affinities. After analyzing the molecular conformations of these 100 ligands, we found that 59 ligands bound to different protein targets without significantly changing conformation, suggesting that there is no distinct correlation between conformational flexibility and polypharmacology within our dataset. Ligands crystallized in similar proteins and highly ligand-efficient compounds with five or fewer rotatable bonds were less likely to adjust conformation when binding.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes of BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608 (USA).
authors.forename: Michael W
authors.initials: MW
authors.lastname: He
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Lee
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
mesh_terms: D001549:Benzamides / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D000068877:Imatinib Mesylate; D019469:Indinavir / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D013451:Sulfonic Acids / Q000737:chemistry / Q000378:metabolism
chemical_list: D001549:Benzamides; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D011506:Proteins; D015800:Protozoan Proteins; D011743:Pyrimidines; D013451:Sulfonic Acids; C437986:indirubin-5-sulfonic acid; D019469:Indinavir; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: PDB; conformation flexibility; ligand design strategy; polypharmacology; selectivity