title: Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors.
abstract: The polo-like kinase 1 (Plk1) is a critical regulator of cell division that is overexpressed in many types of tumors. Thus, a strategy in the treatment of cancer has been to target the kinase activity (ATPase domain) or substrate-binding domain (Polo-box Domain, PBD) of Plk1. However, only few synthetic small molecules have been identified that target the Plk1-PBD. Here, we have applied an integrative approach that combines pharmacophore modeling, molecular docking, virtual screening, and in vitro testing to discover novel Plk1-PBD inhibitors. Nine Plk1-PBD crystal structures were used to generate structure-based hypotheses. A common pharmacophore model (Hypo1) composed of five chemical features was selected from the 9 structure-based hypotheses and used for virtual screening of a drug-like database consisting of 159,757 compounds to identify novel Plk1-PBD inhibitors. The virtual screening technique revealed 9,327 compounds with a maximum fit value of 3 or greater, which were selected and subjected to molecular docking analyses. This approach yielded 93 compounds that made good interactions with critical residues within the Plk1-PBD active site. The testing of these 93 compounds in vitro for their ability to inhibit the Plk1-PBD, showed that many of these compounds had Plk1-PBD inhibitory activity and that compound Chemistry_28272 was the most potent Plk1-PBD inhibitor. Thus Chemistry_28272 and the other top compounds are novel Plk1-PBD inhibitors and could be used for the development of cancer therapeutics.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Sugunadevi
authors.initials: S
authors.lastname: Sakkiah
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Senese
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Qianfan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, South Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, United States of America; Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jorge Z
authors.initials: JZ
authors.lastname: Torres
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D062313:Databases, Pharmaceutical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1