The importance of synthetic drugs for type 2 diabetes drug discovery.
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a major metabolic, multi-causal and heterogeneous disorder which causes significant morbidity and mortality with considerable burden to healthcare resources. The number of deaths due to T2DM highlights the insufficiency of the currently available drugs for controlling the disease and its complications and more needs to be done.


METHODS
This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion on the mechanism of action, side effects and structure of the currently available synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design.


CONCLUSIONS
Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to produce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also been progress with the design and development of novel T2DM therapeutics including: PPARα/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is 'best suited' with each patient responding differently.
Tehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences Research Center , Tehran , Iran.
Maliheh
M
Safavi
Alireza
A
Foroumadi
Mohammad
M
Abdollahi
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors