Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents

Abstract

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

Computational Screening for the Dipeptidyl Peptidase-IV Inhibitory Peptides from Putative Hemp Seed Hydrolyzed Peptidome as a Potential Antidiabetic Agent

“…In addition, Ser630 was located on the nucleophilic elbow, which is essential for DPPIV activity [ 50 ]. Compared to other known DPPIV inhibitor drugs (Sitagliptin, Vildagliptin, and Linagliptin), they were reported to bind to the S 1 , S 2 , and S 2 extensive; S 1 and S 2 ; and S 1 , S 2 , S 1 ’, and S 2 ’ subsites, respectively [ 51 ]. Our results show strong H-bonds between our peptide candidates and several specific residues of the DPPIV active site.…”

Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes Mellitus Management: Pharmacophore Virtual Screening, Molecular Docking, Pharmacokinetic Evaluations, and Conceptual DFT Analysis

“…The mandatory ligand's interactions for DPP-4 inhibition with S1 and S2 subunits were observed both for alogliptin within the 3GB0 binding site, linagliptin within the 2RGU binding site, and sitagliptin within the 1 × 70 binding site. Moreover, alogliptin exhibited additional interactions with the S1' subunit, while linagliptin revealed additional interactions with both S1' and S2' subunits, and in the case of sitagliptin, the additional interactions were observed with the S2 extensive subunit [52,[54][55][56]. The additional interactions between the ligand and DPP-4 subsites indicate an enhanced bioavailability potency and, consequently, encourage the exploration of diverse scaffold structures that can play a pivotal role in facilitating these interactions.…”

Neuroprotective effects of dipeptidyl peptidase 4 inhibitor on Alzheimer’s disease: a narrative review

“…DPP4 has five binding subsites including S1, S2, S1′, S2′, and S2 extensive (Arulmozhiraja et al, 2016). DPP4is interacting with S1 and S2 subsites is mandatory for them to exert their inhibitory activity, and additional interaction with S1′, S2′, or S2 extensive will substantially increase the drug's potency (Mathur et al, 2023). Accordingly, DPP4is were grouped into different classes according to the enzyme subsites where they bind to.…”

“…Accordingly, DPP4is were grouped into different classes according to the enzyme subsites where they bind to. For example, vildagliptin and saxagliptin binding with S1 and S2 only were categorized into Class 1, alogliptin and linagliptin binding with S1′, S2′, S1 and S2 belong to Class 2, and sitagliptin, anagliptin, gemigliptin, and teneligliptin binding with S1, S2 and S2 extensive were classified as Class 3 (Arulmozhiraja et al, 2016;Gallwitz, 2019;Mathur et al, 2023).…”