title: Guide to virtual screening: application to the Akt phosphatase PHLPP.
abstract: We present an example-based description of virtual screening (VS) techniques used to identify new regulators of the Akt phosphatase PHLPP (PH domain Leucine repeat Protein Phosphatase). This enzyme opposes the effects of two kinases, Akt and PKC, which play a major role in cell growth and survival. Therefore, PHLPP is a potential therapeutic target in pathophysiologies where these pathways are either repressed, such as in diabetes and cardiovascular diseases, or over-activated as in cancer. To the best of our knowledge, no PHLPP inhibitors have been reported so far in the literature. In this study, we used a combination of chemical and virtual screening techniques that led to the identification of a number of inhibiting compounds with diverse scaffolds. These compounds bind PHLPP and inhibit cell death when tested in cellular assays. We employed GLIDE docking software to screen a library of more than 40,000 compounds selected from the NCI open depository (250,000 compounds) by similarity searches. We compare the efficiency at which we determined binding compounds from the chemical screen, and compare enrichment factors of the virtually discovered compounds over chemical screening.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA, USA. wsinko@ucsd.edu
authors.forename: William
authors.initials: W
authors.lastname: Sinko
authors.forename: Emma
authors.initials: E
authors.lastname: Sierecki
authors.forename: César A F
authors.initials: CA
authors.lastname: de Oliveira
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000032:analysis / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D040681:Structural Homology, Protein; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases