title: Homology modeling and virtual screening for inhibitors of lipid kinase PI(4)K from Plasmodium.
abstract: Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. Recent studies have shown that KAI715 and its analogs inhibit malaria parasites growth by binding to lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) of the parasites. Therefore, targeting PI(4)K may open up new avenues of target-based drug discovery to identify novel anti-malaria drugs. In this investigation, we describe the discovery of novel potent PfPI(4)K (PI(4)K from P. falciparum) inhibitors by employing a proposed hybrid virtual screening (VS) method, including pharmacophore model, drug-likeness prediction and molecular docking approach. 3D structure of PfPI(4)K has been established by homology modeling. Pharmacophore model HypoA of PfPI(4)K inhibitors has been developed based on the ligand complexed with its corresponding receptor. 174 compounds with good ADMET properties were carefully selected by a hybrid virtual screening method. Finally, the 174 hits were further validated by using a new pharmacophore model HypoB built based on the docking pose of BQR685, and 95 compounds passed the last filter. These compounds would be further evaluated by biological activity assays. The molecular interactions of the top two potential inhibitors with the active site residues are discussed in detail. These identified hits can be further used for designing the more potent inhibitors against PfPI(4)K by scaffold hopping, and deserve consideration for further structure-activity relationship (SAR) studies.
authors.affiliation: College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China; Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China.
authors.forename: Ji-Xia
authors.initials: JX
authors.lastname: Ren
authors.affiliation: Central Laboratory, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing 100038, People's Republic of China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Gao
authors.affiliation: College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Cao
authors.affiliation: College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China.
authors.forename: Quan-An
authors.initials: QA
authors.lastname: Hu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China. Electronic address: yxie@implad.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D015203:Reproducibility of Results; D040681:Structural Homology, Protein
chemical_list: D015778:Minor Histocompatibility Antigens; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase
keywords: Homology modeling; Lipid kinase PI(4)K; Pharmacophore modeling; Virtual screening