title: Implications of the small number of distinct ligand binding pockets in proteins for drug discovery, evolution and biochemical function.
abstract: Coincidence of the properties of ligand binding pockets in native proteins with those in proteins generated by computer simulations without selection for function shows that pockets are a generic protein feature and the number of distinct pockets is small. Similar pockets occur in unrelated protein structures, an observation successfully employed in pocket-based virtual ligand screening. The small number of pockets suggests that off-target interactions among diverse proteins are inherent; kinases, proteases and phosphatases show this prototypical behavior. The ability to repurpose FDA approved drugs is general, and minor side effects cannot be avoided. Finally, the implications to drug discovery are explored.
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30318, USA. Electronic address: skolnick@gatech.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30318, USA.
authors.forename: Mu
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30318, USA.
authors.forename: Ambrish
authors.initials: A
authors.lastname: Roy
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30318, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30318, USA.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D019143:Evolution, Molecular; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011506:Proteins; D011494:Protein Kinases
keywords: Drug repurposing; Drug side effects; Kinases, proteases, phosphatases; Ligand binding pockets; Virtual ligand screening