title: In silico-screening approaches for lead generation: identification of novel allosteric modulators of human-erythrocyte pyruvate kinase.
abstract: Identification of allosteric binding site modulators have gained increased attention lately for their potential to be developed as selective agents with a novel chemotype and targeting perhaps a new and unique binding site with probable fewer side effects. Erythrocyte pyruvate kinase (R-PK) is an important glycolytic enzyme that can be pharmacologically modulated through its allosteric effectors for the treatment of hemolytic anemia, sickle-cell anemia, hypoxia-related diseases, and other disorders arising from erythrocyte PK malfunction. An in-silico screening approach was applied to identify novel allosteric modulators of pyruvate kinase. A small-molecules database of the National Cancer Institute (NCI), was virtually screened based on structure/ligand-based pharmacophore. The virtual screening campaign led to the identification of several compounds with similar pharmacophoric features as fructose-1,6-bisphosphate (FBP), the natural allosteric activator of the kinase. The compounds were subsequently docked into the FBP-binding site using the programs FlexX and GOLD, and their interactions with the protein were analyzed with the energy-scoring function of HINT. Seven promising candidates were obtained from the NCI and subjected to kinetics analysis, which revealed both activators and inhibitors of the R-isozyme of PK (R-PK).
authors: Department of Medicinal Chemistry, School of Pharmacy & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA, USA.
authors: Ashutosh
authors: A
authors: Tripathi
authors: Martin K
authors: MK
authors: Safo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000495:Allosteric Site; D001665:Binding Sites; D004912:Erythrocytes / Q000201:enzymology*; D005635:Fructosediphosphates / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011770:Pyruvate Kinase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005635:Fructosediphosphates; D011770:Pyruvate Kinase; C029063:fructose-1,6-diphosphate