title: Integrating virtual and biochemical screening for protein tyrosine phosphatase inhibitor discovery.
abstract: Protein tyrosine phosphatases (PTPs) represent an important class of enzymes that mediate signal transduction and control diverse aspects of cell behavior. The importance of their activity is exemplified by their significant contribution to disease etiology with over half of all human PTP genes implicated in at least one disease. Small molecule inhibitors targeting individual PTPs are important biological tools, and are needed to fully characterize the function of these enzymes. Moreover, potent and selective PTP inhibitors hold the promise to transform the treatment of many diseases. While numerous methods exist to develop PTP-directed small molecules, we have found that complimentary use of both virtual (in silico) and biochemical (in vitro) screening approaches expedite compound identification and drug development. Here, we summarize methods pertinent to our work and others. Focusing on specific challenges and successes we have experienced, we discuss the considerable caution that must be taken to avoid enrichment of inhibitors that function by non-selective oxidation. We also discuss the utility of using "open" PTP structures to identify active-site directed compounds, a rather unconventional choice for virtual screening. When integrated closely, virtual and biochemical screening can be used in a productive workflow to identify small molecules targeting PTPs.
authors: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI, United States.
authors: Katie R
authors: KR
authors: Martin
authors: Mayo Clinic, Scottsdale, AZ, United States.
authors: Pooja
authors: P
authors: Narang
authors: Mayo Clinic, Scottsdale, AZ, United States.
authors: José L
authors: JL
authors: Medina-Franco
authors: Mayo Clinic, Scottsdale, AZ, United States.
authors: Nathalie
authors: N
authors: Meurice
authors: Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI, United States. Electronic address: jeff.mackeigan@vai.org.
authors: Jeffrey P
authors: JP
authors: MacKeigan
mesh_terms: D001681:Biological Assay / Q000295:instrumentation / Q000379:methods*; D020134:Catalytic Domain; D003198:Computer Simulation; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases
keywords: DTT; HTS; Inhibitor; PDB; PTP; PTPσ; Protein tyrosine phosphatase; RCC; ROS; Small molecule; VS; Virtual screen; dithiothreitol; high-throughput screen; pNPP; pTyr; para-nitrophenyl phosphate; phosphotyrosine; protein data bank; protein tyrosine phosphatase; reactive oxygen species; redox cycling compounds; virtual screening
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