title: Identification of a high affinity selective inhibitor of Polo-like kinase 1 for cancer chemotherapy by computational approach.
abstract: Polo-like kinase (Plk)1 is a key regulator of the cell cycle during mitotic phase and is an attractive anti-mitotic drug target for cancer. Plk1 is a member of Ser/Thr kinase family which also includes Plk2-4 in human. Plk1 promotes the cell division whereas Plk2 and Plk3 are reported to act as tumour suppressors. The available inhibitors of Plk1 also suppress Plk2 and Plk3 activity significantly resulting in the cell death of normal cells in addition to the cancer cells. Hence, it is imperative to explore Plk1 specific inhibitors as anti-cancer drugs. In this work, a selective potential inhibitor of Plk1 has been identified by molecular docking based high throughput virtual screening. The identified compound exploits the subtle differences between the binding sites of Plk1 and other Ser/Thr kinases including Plk2-4. The predicted binding affinity of identified inhibitor is higher than available inhibitors with a 100-fold selectivity towards Plk1 over Plk2-4 and several cell cycle kinases. It also satisfies the Lipinski's criteria of drug-like molecules and passes the other ADMET filters. This triazole compound with aryl substituent belongs to a novel class of potential inhibitor for Plk1. The suggested potential lead molecule can thus be tested and developed further as a potent and selective anti-cancer drug.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India; Department of Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
authors.forename: Sai Prasad
authors.initials: SP
authors.lastname: Pydi
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India.
authors.forename: Tej P
authors.initials: TP
authors.lastname: Singh
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110 029, India. Electronic address: punitkaur1@hotmail.com.
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011621:Pteridines / Q000737:chemistry; D013816:Thermodynamics; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536
keywords: Anti-cancer drugs; Homology modelling; Molecular docking; Molecular dynamics simulation; Polo-like kinase; Structure-based drug design