Saxagliptin: Difference between revisions

<StructureSection load='' size='340' side='right' caption='Saxagliptin, better known as Onglyza, ([[3bjm]])' scene='Saxagliptin/Saxaglilptin/1'>

* Importance: It is the most recent drug treating [[Diabetes]] to be approved by the FDA. Effectiveness at nearly 20-fold lower doses compared to [[Sitagliptin]] & [[Vildagliptin]], allowing for dramatically reduced [[Pharmacokinetics#Cmax|C_max]] and [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] and a potentially improved side effect profile. Increasing evidence that all DPP-4 inhibitors can to certain malignant cancers.<ref>PMID:15735018</ref>

Dipeptidyl Peptidase-4 (DPP-4) is a membrane serine exopeptidase that cleaves proline dipeptides form the N-terminal end of protein substrates. DPP-4 plays a major role in [[Carbohydrate Metabolism|glucose metabolism]] as it is responsible for the degradation of incretins, most notably Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). Incretins are a group of gastrointestinal hormones that stimulate insulin biosynthesis and inhibit glucagon secretion after consuming high glucose meals. Since [[Diabetes]] is typically caused by a deficiency in [[insulin]] secretion or by increased hepatic glucose production, preventing incretin degradation is a viable treatment approach for diabetics. Saxagliptin is a <scene name='Saxagliptin/Dpp4/1'>competitive inhibitor of DPP-4</scene>. By inhibiting DPP-4 and subsequently preventing the enzymatic degradation of GLP-1 and GIP, these incretins are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas, resulting in controlled blood-glucose levels.<ref>PMID:17073841</ref> Saxagliptin binds to the <scene name='Saxagliptin/Act/1'>active site pocket of DPP-4</scene> within a tunnel capable of binding incretin compounds and situating their N-terminus in the active site.<ref>PMID:15634008</ref> This active site contains several <scene name='Saxagliptin/Act2/2'>crucial residues for binding</scene> including: Glu 206, Glu 205, Asp 663, Tyr 662, Asn 710, Val 711, His 740, Trp 629, Ser 630, Try 631, Tyr 547, Tyr 666, & Phe 357. <scene name='Saxagliptin/Bound/5'>Saxagliptin forms</scene> 7 hydrogen bonds with DPP-4 and a rare, reversible covalent bond with Ser 630, which appears to be formed with the help of His 740.<ref>PMID:18227430</ref>