Targeting the purinome.
Purines are critical cofactors in the enzymatic reactions that create and maintain living organisms. In humans, there are approximately 3,266 proteins that utilize purine cofactors and these proteins constitute the so-called purinome. The human purinome encompasses a wide-ranging functional repertoire and many of these proteins are attractive drug targets. For example, it is estimated that 30% of modern drug discovery projects target protein kinases and that modulators of small G-proteins comprise more than 50% of currently marketed drugs. Given the importance of purine-binding proteins to drug discovery, the following review will discuss the forces that mediate protein:purine recognition, the factors that determine druggability of a protein target, and the process of structure-based drug design. A review of purine recognition in representatives of the various purine-binding protein families, as well as the challenges faced in targeting members of the purinome in drug discovery campaigns will also be given.
Murray
Jeremy M
JM
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA, USA.
Bussiere
Dirksen E
DE
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008967:Molecular Biology / Q000379:methods; D008969:Molecular Sequence Data; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects; D011687:Purines / Q000737:chemistry* / Q000378:metabolism; D012985:Software Design; D013816:Thermodynamics; D018631:ras Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics
D008024:Ligands; D011687:Purines; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D010727:Phosphoric Diester Hydrolases; D018631:ras Proteins