Potent Dipeptidyl Peptidase IV Inhibitors Research Articles

Purification and Identification of Novel Dipeptidyl Peptidase IV Inhibitory Peptides Derived from Bighead Carp (Hypophthalmichthys nobilis).

Dipeptidyl peptidase IV (DPP-IV) inhibitors are widely used in treating type 2 diabetes due to their ability to lower blood glucose levels. However, synthetic versions often lead to gastrointestinal side effects. This study explores DPP-IV inhibitory properties in peptides from bighead carp skin. Collagen was prepared, hydrolyzed into collagen peptides, and then fractionated for DPP-IV inhibitory activity examination. The most effective fractions were identified, and their peptide sequences were determined. Molecular docking analysis identified nine peptides with potential inhibitory activity, four of which (VYP, FVA, PPGF, PGLVG) were synthesized and tested in vitro. PPGF exhibited the highest potency with an IC50 of 4.63 nM, competitively binding to key DPP-IV sites, including ARG125, VAL711, TYR666, and TYR662. Other peptides showed varying effectiveness, with IC50 values of 398.87 nM (VYP), 402.02 nM (FVA), and 110.20 nM (PGLVG). These findings highlight bighead carp skin peptides as potent DPP-IV inhibitors with hypoglycemic potential, suggesting a novel avenue for diabetes management using natural peptides. Moreover, this research underscores the utilization of bighead carp by-products, contributing to environmental sustainability.

Design of some Apigenin derivatives as selective DPP-IV Inhibitors by Pharmacophore Modelling and its Validation through Molecular Dynamics Simulation

One of the most common forms of diabetes, type-2 diabetes mellitus is a chronic metabolic condition brought on by problems with insulin production or insulin resistance. By modifying blood glucose homeostasis, dipeptidyl peptidase-IV (DPP-IV) inhibition has the potential to treat type 2 diabetes. The quick development of computational drug design provided a fantastic opportunity to both discover and forecast the effectiveness of potential DPP-IV inhibitors. The current investigation supports and verifies the identification of new Apigenin derivatives as selective DPP-IV inhibitors. Schrodinger software was used to perform virtual screening (VS) of created compounds against DPP-IV, and the most promising hits were chosen. Out of 110 substances, 56 new apigenin derivatives were chosen for additional docking investigations using Glide based on their selectivity threshold followed by validation by pose selection method which is found to be below 2 Ǻ based on their superimposion with co-crystallized lgand. The DPP-IV protein was used as the target of molecular dynamic (MD) simulation studies to evaluate the correct binding mechanisms and stability of their complexes with enzyme. Structural chemistry was utilised to guide and considerably speed up the drug discovery process during the back-up development stages. It was also used to analyse in-silico suggestions and screening results, as well as to come up with fresh ideas. The study thus demonstrates the possibility of apigenin derivatives as highly specific DPP-IV inhibitors.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Phytochemicals from Amberboa ramosa as potential DPP-IV inhibitors for the management of Type-II diabetes mellitus: Inferences from in-silico investigations

Diabetes is a chronic metabolic disorder, and as per the global burden, it is estimated that around 462 million people will be affected due to the cause of this disease. Currently, several drug treatments are available, but the need for herbal medicine is required for the management of diabetes. The present study focuses on the identification of potential compounds from the Amberboa ramosa plant and weed out similar potential compounds from a phytochemical library based on the best hits from the selected plant for the inhibition of dipeptidyl peptidase-IV (DPP-IV) enzyme using computational approaches. The results demonstrate that 3β,4α,8α-trihydroxy-4β-(hydroxymethyl)-1αH,5αH,6βH,7αH-guai-10(14),11(13)‑dien-6,12-olide (Compound 1) and 5‑hydroxy-7,8-dimethoxyflavone (Compound 2) showed maximum binding energy and dock score among all the compounds obtained from A. ramosa whereas, NPC170675 (Compound 3) was obtained from the phytochemical library. The molecular dynamics reveal that among all the three compounds, the root mean square deviation (RMSD) of compound 3 was found to be stable after 20 ns throughout the simulation. Compound 2 from A. ramosa was found to be more stable as compared to compound 1 in the active site during the simulation of 100 ns. Among all the three phytocompounds, compound 2 possesses lowest ΔGBind energy of -51.096 kcal/mol in the post-simulation binding free energy analysis. The molecular reactivity analysis using hybrid QMMM approach shows compound 2 has the highest softness value in both the free (6.410 eV) and bound (6.817 eV) states, as well as the lowest hardness (0.078 eV/0.073 eV) and HOMO–LUMO gap (0.156 eV), indicating that it is more reactive than the others. Hence, compound 2 from A. ramosa is the most validated ligand from the in-silico findings. Thus, the exploration of phytoconstituents from A. ramosa plant and phytochemical library could be used in the management of Type-II diabetes mellitus.

In-silico Exploration of Phytoconstituents of Gymnema sylvestre as Potential Glucokinase Activators and DPP-IV Inhibitors for the Future Synthesis of Silver Nanoparticles for the Treatment of Type 2 Diabetes Mellitus

Background: Diabetes has a large death toll worldwide, particularly as it falls into the ten leading causes of death. Type 2 diabetes mellitus (T2DM) occurs as the body becomes resistant to insulin and sugar accumulates in the blood. It has been observed that dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucokinase activators are known therapeutic agents to treat T2DM. Among the possible medicinal plants, Gymnema sylvestre (GyS) belongs to the Apocynaceae family and is traditionally used for the treatment of different diseases. This plant is also known as “Gurmur” because it has a sugarreducing ability. GyS is known to be one of the main botanicals for the treatment of diabetes. Objective: Considering the studies described above, we have tried to investigate the natural DPP-IV inhibitors and potent glucokinase activators from the phytoconstituents of GyS. New drug candidates from the medicinal plant GyS have been reported as potent DPP-IV inhibitors and glucokinase activators. Methods: As a preliminary investigation, we have studied the effectiveness of phytoconstituents of GyS in T2DM through molecular docking as a proof of concept of synthesizing silver nanoparticles (for the treatment of T2DM) using an extract of this plant. Results: The present investigative research shows that the recognized compounds included in the present analysis have important values in the treatment of diabetes mellitus. The nine compounds selected are evaluated on the basis of DPP-IV and glucokinase enzyme binding energy values and their drug properties. Except for quercitol, all the selected compounds have exhibited much more potent glucokinase activation potential than their native ligands. Gymnemasin A, lupeol, gymnemoside A, gymnemasaponin V, and gymnemic acid I have shown excellent DPP-IV inhibitory potential. Conclusion: We aimed to synthesize the silver nanoparticles from the leaf extract of GyS for the treatment of T2DM. As a preliminary investigation, we have studied the effectiveness of phytoconstituents of GyS in T2DM through molecular docking as proof of synthesizing silver nanoparticles (for the treatment of T2DM) using an extract of this plant. As a result of the present investigation, it has been concluded that these compounds can be used to treat T2DM, and hence, in the future, we can synthesize the silver nanoparticles from the GyS extract for the treatment of T2DM.

An Integrated Peptidomics and In Silico Approach to Identify Novel Anti-Diabetic Peptides in Parmigiano-Reggiano Cheese.

Simple SummaryDietary habits and sedentary lifestyle are widely established to be the major risk factors for the development of long-term chronic conditions, such as type-2 diabetes (T2D). In this framework, where consumer’s food choices are even more influenced by an ever-growing awareness on nutritional, environmental, and healthy aspects, the presence and identification of natural bioactive compounds are gaining increasing attention in the scientific community. Pharmacological treatment of T2D is based on the administration of molecules able to inhibit some key enzymes involved in the carbohydrate digestion and insulin secretion. The multiple side-effects of synthetic inhibitors led to an increased demand for natural food-derived anti-diabetic agents. The present work offers a new integrated approach for the identification and selection of new bioactive peptides, able to inhibit the key digestive enzymes implicated in the control of blood glucose level. The novelty lies in the development of a new, quick, and cost-effective integrated methodology supported by confirmed in vitro evidence. In fact, the present work successfully accomplished the identification of two selected candidates with a possible application in the diabetes management. Indeed, the functional and healthy role of Parmigiano-Reggiano cheese in human nutrition was assessed, highlighting its potential anti-diabetic properties.Inhibition of key metabolic enzymes linked to type-2-diabetes (T2D) by food-derived compounds is a preventive emerging strategy in the management of T2D. Here, the impact of Parmigiano-Reggiano (PR) cheese peptide fractions, at four different ripening times (12, 18, 24, and 30 months), on the enzymatic activity of α-glucosidase, α-amylase, and dipeptidyl peptidase-IV (DPP-IV) as well as on the formation of fluorescent advanced glycation end-products (fAGEs) was assessed. The PR peptide fractions were able to inhibit the selected enzymes and fAGEs formation. The 12-month-ripening PR sample was the most active against the three enzymes and fAGEs. Mass spectrometry analysis enabled the identification of 415 unique peptides, 54.9% of them common to the four PR samples. Forty-nine previously identified bioactive peptides were found, mostly characterized as angiotensin-converting enzyme-inhibitors. The application of an integrated approach that combined peptidomics, in silico analysis, and a structure–activity relationship led to an efficient selection of 6 peptides with potential DPP-IV and α-glucosidase inhibitory activities. Peptide APFPE was identified as a potent novel DPP-IV inhibitor (IC50 = 49.5 ± 0.5 μmol/L). In addition, the well-known anti-hypertensive tripeptide, IPP, was the only one able to inhibit the three digestive enzymes, highlighting its possible new and pivotal role in diabetes management.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation.

Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein, and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduce the deterioration of gutderived endogenous incretin hormones secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of the pancreas. In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities against the DPP-IV enzyme. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 μM concentration, where compound 3d harboring ortho- fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669, and Y752 backbones Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Synthesis, Biological Evaluation, and QPLD Studies of Piperazine Derivatives as Potential DPP-IV Inhibitors.

Diabetes mellitus is a serious global health issue, currently affecting 425 million people and is set to affect over 690 million people by 2045. It is a chronic disease characterized by hyperglycemia due to relative or absolute insulin hormone deficiency. Dipeptidyl peptidase- IV (DPP-IV) inhibitors are hypoglycemic agents augmenting the action of the incretin hormones that stimulate insulin secretion from the pancreatic beta cells. In this study, synthesis and biological evaluation of seven piperazine derivatives 3a-g was carried out. The synthesized molecules were characterized using proton-nuclear magnetic resonance, carbon-nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. In vitro biological evaluation study showed comparable DPP-IV inhibitory activity for the targeted compounds ranging from 19%-30% at 100 μM concentration. Furthermore, the in vivo hypoglycemic activity of 3d was evaluated using streptozotocin-induced diabetic mice. It was found that compound 3d significantly decreased the blood glucose level when the diabetic group treated with 3d was compared to the control diabetic group. Quantum-Polarized Ligand Docking (QPLD) studies demonstrate that 3a-g fit the binding site of DPP-IV enzyme and form H-bonding with the backbones of R125, E205, E206, K554, W629, Y631, Y662, R669, and Y752. Piperazine derivatives were successfully found to be new scaffolds as potential DPP-IV inhibitors.

Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated in silico approaches

The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC50: 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.AbbreviationsADMEabsorption, distribution, metabolism and excretionChEBIchemical entities of biological interestDPP-IVdipeptidyl peptidase IVDISCOtechdistance comparisonsHTVShigh throughput virtual screeningMDmolecular dynamicsMM-GBSAmolecular mechanics‐generalized born surface areaOGTToral glucose tolerance testPBVSpharmacophore-based virtual screeningPDBprotein data bankRMSDroot mean square deviationROCreceiver operating characteristicsSPstandard precisionSBVSstructure-based virtual screeningVSvirtual screeningXPextra precisionCommunicated by Ramaswamy H. Sarma

Optimization of the benzamide fragment targeting the S2′ site leads to potent dipeptidyl peptidase-IV inhibitors

Our recently successful identification of benzoic acid-based DPP-4 inhibitors spurs the further quest for in-depth structure-activity relationships (SAR) study in S2' site DPP-4. Thus novel benzamide fragments were designed to target the S2' site to compromise lipophilicity and improve oral activity. Exploring SAR by introduction of a variety of amide and halogen on benzene ring led to identification of several compounds, exerting moderated to excellent DPP-4 activities, in which 4'-chlorine substituted methyl amide 17g showed most potent DPP-4 activity with the IC50 value of 1.6 nM. Its activity was superior to reference alogliptin. Docking study ideally verified and interpreted the obtained SAR of designed compounds. As a continuation, DPP-8/9 assays revealed the designed compounds exhibited good selectivity over DPP-8 and DPP-9. Subsequent cell-based test indicated compound 17g displayed low toxicity toward the LO2 cell line up to 100 μM. In vivo evaluation showed compound 17g robustly improved the glucose tolerance in normal mice. Importantly, 17g exhibited reasonable pharmacokinetic (PK) profiles for oral delivery. Overall, compound 17g has the potential to a safe and efficacious DPP-4 inhibitor for T2DM treatment.

Discovery of Food-Derived Dipeptidyl Peptidase IV Inhibitory Peptides: A Review.

Diabetes is a chronic metabolic disorder which leads to high blood sugar levels over a prolonged period. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and results from the body’s ineffective use of insulin. Over ten dipeptidyl peptidase IV (DPP-IV) inhibitory drugs have been developed and marketed around the world in the past decade. However, owing to the reported adverse effects of the synthetic DPP-IV inhibitors, attempts have been made to find DPP-IV inhibitors from natural sources. Food-derived components, such as protein hydrolysates (peptides), have been suggested as potential DPP-IV inhibitors which can help manage blood glucose levels. This review focuses on the methods of discovery of food-derived DPP-IV inhibitory peptides, including fractionation and purification approaches, in silico analysis methods, in vivo studies, and the bioavailability of these food-derived peptides. Moreover, food-derived DPP-IV inhibitory peptides discovered during this decade are listed and distributed in a 3D scatter plot graph based on their IC50, molecular weight, and grand average of hydropathicity values, which can help us to understand the relationship between the features of the peptides and their activities.

Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors.

Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50 = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.

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

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 IC50 ≤ 100nM). 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.

Ephedrine as a lead compound for the development of new DPP-IV inhibitors.

Extracts from Ephedra species have been reported to be effective as antidiabetics. A previous in silico study predicted that ephedrine and five ephedrine derivatives could contribute to the described antidiabetic effect of Ephedra extracts by inhibiting dipeptidyl peptidase IV (DPP-IV). Finding selective DPP-IV inhibitors is a current therapeutic strategy for Type 2 diabetes mellitus management. Therefore, the main aim of this work is to experimentally determine whether these alkaloids are DPP-IV inhibitors. Materials& methods: The DPP-IV inhibition ofEphedra's alkaloids was determined via a competitive-binding assay. Then, computational analyses were used in order to find out the protein-ligand interactions and to perform a lead optimization. Our results show that all six molecules are DPP-IV inhibitors, with IC50 ranging from 124μM for ephedrine to 28 mM for N-methylpseudoephedrine. Further computational analysis shows how Ephedra's alkaloids could be used as promising lead molecules for designing more potent and selective DPP-IV inhibitors.

Rapid Identification of Dipeptidyl Peptidase-IV (DPP-IV) Inhibitory Peptides from Ruditapes philippinarum Hydrolysate.

Dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides were rapidly identified from Ruditapes philippinarum hydrolysate. The hydrolysate was fractionated by ethanol precipitation and preparative reverse phase high-performance liquid chromatography (RP-HPLC). The fraction which showed the highest DPP-IV inhibitory activity was then analyzed by a high-throughput nano-liquid chromatography electrospray ionization tandem mass spectrometry (nano-LC ESI-MS/MS) method, and the sequences of peptides were identified based on the MS/MS spectra against the Mollusca protein data from the UniProt database. In total, 50 peptides were identified. Furthermore, molecular docking was used to identify potential DPP-IV inhibitors from the identified peptides. Docking results suggested that four peptides: FAGDDAPR, LAPSTM, FAGDDAPRA, and FLMESH, could bind pockets of DPP-IV through hydrogen bonds, π-π bonds, and charge interactions. The four peptides were chemically synthesized and tested for DPP-IV inhibitory activity. The results showed that they possessed DPP-IV inhibitory activity with IC50 values of 168.72 μM, 140.82 μM, 393.30 μM, and >500 μM, respectively. These results indicate that R. philippinarum-derived peptides may have potential as functional food ingredients for the prevention of diabetes.

Computational Analysis of Gynura bicolor Bioactive Compounds as Dipeptidyl Peptidase-IV Inhibitor.

The inhibition of dipeptidyl peptidase-IV (DPPIV) is a popular route for the treatment of type-2 diabetes. Commercially available gliptin-based drugs such as sitagliptin, anagliptin, linagliptin, saxagliptin, and alogliptin were specifically developed as DPPIV inhibitors for diabetic patients. The use of Gynura bicolor in treating diabetes had been reported in various in vitro experiments. However, an understanding of the inhibitory actions of G. bicolor bioactive compounds on DPPIV is still lacking and this may provide crucial information for the development of more potent and natural sources of DPPIV inhibitors. Evaluation of G. bicolor bioactive compounds for potent DPPIV inhibitors was computationally conducted using Lead IT and iGEMDOCK software, and the best free-binding energy scores for G. bicolor bioactive compounds were evaluated in comparison with the commercial DPPIV inhibitors, sitagliptin, anagliptin, linagliptin, saxagliptin, and alogliptin. Drug-likeness and absorption, distribution, metabolism, and excretion (ADME) analysis were also performed. Based on molecular docking analysis, four of the identified bioactive compounds in G. bicolor, 3-caffeoylquinic acid, 5-O-caffeoylquinic acid, 3,4-dicaffeoylquinic acid, and trans-5-p-coumaroylquinic acid, resulted in lower free-binding energy scores when compared with two of the commercially available gliptin inhibitors. The results revealed that bioactive compounds in G. bicolor are potential natural inhibitors of DPPIV.

Structural Requirements for some 3-amino-N-substituted-4-(substituted phenyl) Butanamides as Dipeptidyl Peptidase-IV Inhibitors Using 3D-QSAR and Molecular Docking Approaches

Dipeptidyl peptidase-IV is well thought out as one of the key targets for treatment of type 2 diabetes mellitus and diverse scaffolds have proven effective in designing novel dipeptidyl peptidase-IV inhibitors. To this end, three dimensional quantitative structure activity relationship analysis and molecular docking studies were performed on a set of 3-amino-N-substituted- 4-(substituted phenyl) butanamides to explore the structural requirements for dipeptidyl peptidase-IV inhibitory activity using k-nearest neighbour molecular field analysis and AutoDock Vina, respectively. The compounds were arbitrarily assigned to active, moderately active and less active classes according to their biological activities. The most significant k-nearest neighbour model exhibited internal cross validation coefficient (q2) and external cross validation coefficient (pred_r2) as 0.67 and 0.82, respectively while the best partial least squares regression model showed 70% internal and 77% external predictability. Subsequent rigorous external validation through q2(F2), q2(F3), concordance correlation coefficient and mean absolute error provided further confidence in the predictability of both the models. Apropos the docking results, the compounds from active, moderately active and less active classes exhibited different binding patterns. Whereas the active compounds such as 12x and 12v occupied a similar space in the active site cavity as the crystallographic ligand (sitagliptin) (PDBID:1X70); the binding modes of compounds from moderately active and inactive classes were distinct from the latter. The findings of this study can provide an impetus for design of prospective potent dipeptidyl peptidase-IV inhibitors.

Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors

Inhibition of dipeptidyl peptidase-IV (DPP-IV) prevents the inactivation of gastric inhibitory polypeptide (GIP) and glucagon-like peptide–1 (GLP-1). This increases circulating levels of active GLP-1 and GIP and stimulates insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. In this study, pharmacophore modeling and docking experiments were carried out and a series of eight novel 2-ethoxy-6,9-disubstituted acridines (13, 15, and 17a–17f) have been designed and synthesized. Then, these compounds were evaluated for their ability to inhibit DPP-IV. Most of the synthesized compounds were proven to have anti-DPP-IV activity where compound 17b displayed the best activity of 43.8% inhibition at 30 μmol/L concentration. Results of this work might be helpful for further optimization to develop more potent DPP-IV inhibitors.

De Novo Design of High Potent DPP-IV Inhibitors Based on the Scaffold of Cyanopyrrolidine

Dipeptidyl peptidase IV (DPP-IV) is an attractive target, and its launched inhibitors have made great significance to clinical therapy of type 2 diabetes. For developing high potent DPP-IV inhibitors, ligand- and structure-based approaches were applied for the optimization of cyanopyrrolidine in this study. Two statistically significant 3D-QSAR models (CoMFA with q2, 0.585; r2, 0.963; CoMSIA with q2, 0.678; r2, 0.949) were developed. In combination with the structure-based pharmacophore model, fundamental structural requirements and pharmacophoric features for R groups were determined. Suitable fragments for different R groups were retrieved for the generation of novel molecules. After being evaluated by molecular docking, QuaSAR descriptors filter and 3D-QSAR activity prediction, active DPP-IV inhibitors were found. The reliability indicated this workflow can be applied to facilitate lead optimization for DPP-IV and even for other drug targets. Keywords: DPP-IV, 3D-QSAR, pharmacophore, fragment, type 2 diabetes.

In silico approaches to predict the potential of milk protein-derived peptides as dipeptidyl peptidase IV (DPP-IV) inhibitors

Molecular docking of a library of all 8000 possible tripeptides to the active site of DPP-IV was used to determine their binding potential. A number of tripeptides were selected for experimental testing, however, there was no direct correlation between the Vina score and their in vitro DPP-IV inhibitory properties. While Trp-Trp-Trp, the peptide with the best docking score, was a moderate DPP-IV inhibitor (IC50 216μM), Lineweaver and Burk analysis revealed its action to be non-competitive. This suggested that it may not bind to the active site of DPP-IV as assumed in the docking prediction. Furthermore, there was no significant link between DPP-IV inhibition and the physicochemical properties of the peptides (molecular mass, hydrophobicity, hydrophobic moment (μH), isoelectric point (pI) and charge). LIGPLOTs indicated that competitive inhibitory peptides were predicted to have both hydrophobic and hydrogen bond interactions with the active site of DPP-IV. DPP-IV inhibitory peptides generally had a hydrophobic or aromatic amino acid at the N-terminus, preferentially a Trp for non-competitive inhibitors and a broader range of residues for competitive inhibitors (Ile, Leu, Val, Phe, Trp or Tyr). Two of the potent DPP-IV inhibitors, Ile-Pro-Ile and Trp-Pro (IC50 values of 3.5 and 44.2μM, respectively), were predicted to be gastrointestinally/intestinally stable. This work highlights the needs to test the assumptions (i.e. competitive binding) of any integrated strategy of computational and experimental screening, in optimizing screening. Future strategies targeting allosteric mechanisms may need to rely more on structure–activity relationship modeling, rather than on docking, in computationally selecting peptides for screening.