Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening.
Dual-specificity phosphatases (DSPs) are important, but poorly understood, cell signaling enzymes that remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Deregulation of DSPs has been implicated in cancer, obesity, diabetes, inflammation, and Alzheimer's disease. Due to their biological and biomedical significance, DSPs have increasingly become the subject of drug discovery high-throughput screening (HTS) and focused compound library development efforts. Progress in identifying selective and potent DSP inhibitors has, however, been restricted by the lack of sufficient structural data on inhibitor-bound DSPs. The shallow, almost flat, substrate binding sites in DSPs have been a major factor in hampering the rational design and the experimental development of active site inhibitors. Recent experimental and virtual HTS studies, as well as advances in molecular modeling, provide new insights into the potential mechanisms for substrate recognition and binding by this important class of enzymes. We present herein an overview of the progress, along with a brief description of applications to two types of DSPs: Cdc25 and MAP kinase phosphatase (MKP) family members. In particular, we focus on combined computational and experimental efforts for designing Cdc25B and MKP-1 inhibitors and understanding their mechanisms of interactions with their target proteins. These studies emphasize the utility of developing computational models and methods that meet the two major challenges currently faced in structure-based in silico design of lead compounds: the conformational flexibility of the target protein and the entropic contribution to the selection and stabilization of particular bound conformers.
Department of Computational Biology, School of Medicine, University of Pittsburgh, 3064 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15213, USA.
Ahmet
A
Bakan
John S
JS
Lazo
Peter
P
Wipf
Kay M
KM
Brummond
Ivet
I
Bahar
D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D020687:cdc25 Phosphatases