Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome

Sattigeri, Jitendra A.; Sethi, Sachin; Davis, Joseph A.; Ahmed, Shahadat; Rayasam, Geeta Vani; Jadhav, Balasaheb G.; Chilla, Satya Narayana Murthy; Datta, Dhrubajyoti; Gadhave, A.; Tulasi, Vamshi Krishna; Jain, Tarun; Voleti, Sreedhara R.; Benjamin, Biju; Udupa, Sunitha; Jain, Garima; Singh, Yogendra; Srinivas, Kona S; Bansal, Vinay S.; Ray, Abhijit; Bhatnagar, Pradip K.; Cliffe, Ian A.

doi:10.1016/j.bmcl.2017.04.036

Cited by 16 publications

(18 citation statements)

References 22 publications

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“…Other studies have demonstrated their therapeutic effects on obesity, neuropathy, and hepatic and renal pathologies. Recent studies have also shown that it is possible to design DPP‐IV inhibitors with dual bioactivity on other targets involved in cardiovascular diseases like ACE or β‐adrenergic receptors …”

Section: Introductionmentioning

confidence: 99%

“…Virtual screening (VS) has been used over recent years to discover DPP‐IV inhibitors in molecular databases, with most of the inhibitors identified having bioactivity in the μM range (see Table , but with no measurement of their selectivity over related enzymes like DPP8 and DPP9 (inhibition of either DPP8 or DPP9 has been suggested as responsible for alopecia, thrombocytopenia, reticulocytopenia, multiorgan histopathological changes, enlarged spleen, and mortality in rats and gastrointestinal toxicity in dogs, while DPP9 inhibition produces neonatal lethality in mice) . In contrast, several recent structure–activity studies (SAR) in the literature describe the synthesis of novel and selective compounds with nM activity as DPP‐IV inhibitors …”

Section: Introductionmentioning

confidence: 99%

“…This is of interest, for instance, when it comes to finding potent and selective DPP‐IV inhibitors of natural origin that could be used as bioactive compounds in functional food design (in which the chemical modification of bioactive molecules to improve their potency and selectivity is not allowed), and also for finding lead molecules that only need minor changes in their structure before they go to preclinical assays (thereby keeping to a minimum the costs and time needed for new DPP‐IV inhibitors to arrive on the market). For instance, these “ minor changes ” would be related to achieve polypharmacology (like has been recently suggested for dual DPP‐IV/ACE inhibitors or for β‐blockers/DPP‐IV inhibitors).…”

Section: Introductionmentioning

confidence: 99%

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Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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“…The results demonstrated that long-term treatment with teneligliptin significantly improved endothelial dysfunction and glucose metabolism in a rat model of metabolic syndrome suggesting that teneligliptin treatment might be beneficial for patients with hypertension and/ or diabetes [33]. Recently Sattigeri et al developed chimeric DPP4/ angiotensin-converting enzyme inhibitors for treating metabolic syndrome by rational de novo synthesis exhibiting polypharmacology to address multifactorial diseases (hyperglycemia, hypertension, and dyslipidemia) [4].…”

Section: Dpp4 Inhibitors In the Management Of Hyperlipidemiamentioning

confidence: 99%

“…Identifying drug candidates exhibiting polypharmacology could be one of the strategies beneficial to address multifactorial diseases as indicated in Table 1. As a consequence, availability of a single therapeutic agent which would simultaneously ameliorate the pharmacological processes contributing to multifactorial diseases could be a significant step forward in the treatment of metabolic syndrome [4].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase-4 Inhibitors: Potential for Treatment of Metabolic Syndrome and Developed Formulation Approaches

Mishra

Dhole

2017

Asian J Pharm Clin Res

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This review article deals with the pre-clinical and clinical findings reviewed or investigated by the researchers on dipeptidyl peptidase-4 (DPP4) inhibitors as a potential in the treatment of metabolic syndrome. Most of the researchers reported the activity of DPP4 inhibitors in the management of obesity, hyperlipidemia, hypertension, atherosclerosis, and in cardiometabolic risk which are summarized in the article. This article also focuses on the formulation approaches in which the formulators have reported and used in the designing or development of DPP4 inhibitors as dosage form. The formulation approaches which are commonly employed on DPP4 inhibitors are immediate release, sustain release, and combination therapy.

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Identification of DPP‐IV inhibitory peptides derived from buffalo colostrum: Mining through bioinformatics, in silico and in vitro approaches

Ashok,

H. S.

2024

J of Molecular Recognition

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Bioactive peptides derived from foods provide physiological health benefits beyond nutrition. This study focused on profiling small peptide inhibitors against two key serine proteases, dipeptidyl peptidase‐IV (DPP‐IV) and prolyl oligopeptidase (POP). DPP‐IV is a well‐known protein involved in diverse pathways regulating inflammation, renal, cardiovascular physiology, and glucose homeostasis. POP is yet another key target protein for neurodegenerative disorders. The study evaluated peptide libraries of buffalo colostrum whey and fat globule membrane proteins derived from pepsin and pepsin–pancreatin digestion through in silico web tools and structure‐based analysis by molecular docking and binding free‐energy estimation, followed by in vitro assay for DPP‐IV inhibition for the lead peptides. The bioinformatic study indicated 49 peptides presented motifs with DPP‐IV inhibition while 5 peptides with sequences for POP inhibition. In the molecular docking interactions study, 22 peptides interacted with active site residues of DPP‐IV and 3 peptides with that of POP. The synthesized peptides, SFVSEVPEL and LTFQHNF inhibited DPP‐IV in vitro with an IC50 of 193.5 μM and 1.782 mM, respectively. The study revealed the key residues for inhibition of DPP‐IV and POP thus affirming the DPP‐IV inhibitory potential of milk‐derived peptides.

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Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome

Cited by 16 publications

References 22 publications

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Dipeptidyl Peptidase-4 Inhibitors: Potential for Treatment of Metabolic Syndrome and Developed Formulation Approaches

Identification of DPP‐IV inhibitory peptides derived from buffalo colostrum: Mining through bioinformatics, in silico and in vitro approaches

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