title: Novel virtual lead identification in the discovery of hematopoietic cell kinase (HCK) inhibitors: application of 3D QSAR and molecular dynamics simulation.
abstract: High level of hematopoietic cell kinase (Hck) is associated with drug resistance in chronic myeloid leukemia. Additionally, Hck activity has also been connected with the pathogenesis of HIV-1 and chronic obstructive pulmonary disease. In this study, three-dimensional (3D) QSAR pharmacophore models were generated for Hck based on experimentally known inhibitors. A best pharmacophore model, Hypo1, was developed with high correlation coefficient (0.975), Low RMS deviation (0.60) and large cost difference (49.31), containing three ring aromatic and one hydrophobic aliphatic feature. It was further validated by the test set (r = 0.96) and Fisher's randomization method (95%). Hypo 1 was used as a 3D query for screening the chemical databases, and the hits were further screened by applying Lipinski's rule of five and ADMET properties. Selected hit compounds were subjected to molecular docking to identify binding conformations in the active site. Finally, the appropriate binding modes of final hit compounds were revealed by molecular dynamics (MD) simulations and free energy calculation studies. Hence, we propose the final three hit compounds as virtual candidates for Hck inhibitors.
authors.affiliation: a Division of Applied Life Science (BK21 Plus 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 , Republic of Korea.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bavi
authors.affiliation: a Division of Applied Life Science (BK21 Plus 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 , Republic of Korea.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: a Division of Applied Life Science (BK21 Plus 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 , Republic of Korea.
authors.forename: Shailima
authors.initials: S
authors.lastname: Rampogu
authors.affiliation: b Department of Science Education , Kyungnam University , Masan , Republic of Korea.
authors.forename: Yongseong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: c Department of Chemical Engineering , Kangwon National University , Chunchon , Republic of Korea.
authors.forename: Yong Jung
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: d Department of Internal Medicine, College of Medicine , Busan Paik Hospital, Inje University , Republic of Korea.
authors.forename: Seok Ju
authors.initials: SJ
authors.lastname: Park
authors.affiliation: a Division of Applied Life Science (BK21 Plus 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 , Republic of Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D062126:Databases, Chemical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D021281:Quantitative Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D047428:Protein Kinase Inhibitors; D051572:Proto-Oncogene Proteins c-hck
keywords: 3D QSAR; Hck; free energy calculations; molecular docking; molecular dynamics simulation; virtual screening