Structure based lead optimization approach in discovery of selective DPP4 inhibitors

Area of Science:

• Pharmacology
• Endocrinology
• Medicinal Chemistry

Background:

• Diabetes mellitus is a chronic metabolic disorder with significant health and societal impact.
• Current oral antidiabetic drugs have limitations, targeting either insulin resistance or deficiency.
• Dipeptidyl peptidase-4 (DPP-4) inhibitors show promise for type 2 diabetes due to a lower risk of hypoglycemia.

Purpose of the Study:

• To review advanced lead candidates of dipeptidyl peptidase (DPP) inhibitors.
• To analyze their binding affinity with target active site residues.
• To guide the discovery of potent, selective, and safer DPP-4 inhibitors through lead optimization.

Main Methods:

• Literature review of DPP inhibitors and their development.
• Analysis of binding affinity data for DPP inhibitor candidates.
• Focus on lead optimization strategies for novel DPP-4 inhibitors.

Main Results:

• Several DPP-4 inhibitors are in use or under investigation.
• Other DPP enzymes (DPP II, FAP, DPP-8, DPP-9) are associated with side effects and toxicity.
• Understanding binding site interactions is crucial for drug design.

Conclusions:

• DPP-4 inhibitors represent a significant advancement in type 2 diabetes management.
• Innovative approaches are needed to design potent, selective, and safer DPP inhibitors.
• Lead optimization based on binding affinity is key to discovering novel antidiabetic drugs.