key: cord-0789163-b3o0vtob authors: Lin, Shian-Ren; Chang, Chia-Hsiang; Tsai, May-Jwan; Cheng, Henrich; Chen, Jian-Chyi; Leong, Max K.; Weng, Ching-Feng title: The perceptions of natural compounds against dipeptidyl peptidase 4 in diabetes: from in silico to in vivo date: 2019-09-19 journal: Ther Adv Chronic Dis DOI: 10.1177/2040622319875305 sha: 570064e6a308ec28efcc76ef74ba3f0e6ea5e5a5 doc_id: 789163 cord_uid: b3o0vtob Dipeptidyl peptidase IV (DPP-4), an incretin glucagon-like peptide-1 (GLP-1) degrading enzyme, contains two forms and it can exert various physiological functions particular in controlling blood glucose through the action of GLP-1. In diabetic use, the DPP-4 inhibitor can block the DDP-4 to attenuate GLP-1 degradation and prolong GLP-1 its action and sensitize insulin activity for the purpose of lowering blood glucose. Nonetheless the adverse effects of DPP-4 inhibitors severely hinder their clinical applications, and notably there is a clinical demand for novel DPP-4 inhibitors from various sources including chemical synthesis, herbs, and plants with fewer side effects. In this review, we highlight various strategies, namely computational biology (in silico), in vitro enzymatic and cell assays, and in vivo animal tests, for seeking natural DPP-4 inhibitors from botanic sources including herbs and plants. The pros and cons of all approaches for new inhibitor candidates or hits will be under discussion. According to the statistics from International Diabetes Federation (IDF), there were 425 million diabetes mellitus (DM) patients in 2017 worldwide, and that number is expected to increase to 629 million by 2045. 1 Abnormally high blood glucose caused by insulin insufficiency or insensitivity can lead to severe complications such as chronic renal failure, microvascular complication, cerebrovascular accident, and infarction induced by high glycated serum and blood vessel proteins. 2, 3 Moreover, insufficient insulin signal leads to the decreased glucose uptake from the blood that, in turn, can result in ulcers, gangrene, diabetic retinopathy, and neuropathy. 2 Recent DM treatment is inclined to maintain the blood glucose level within normal limits by (e.g. nutritional therapy and physical management) and medication due to the incurable nature of DM. 4, 5 Diabetic medications can be characterized into five strategies based on their acting mechanisms: raising insulin secretion (e.g. sulfonylurea and meglitinide analogs), reducing intestinal glucose absorption (e.g. acarbose), triggering insulin-independent glucose uptake signaling (e.g. thiazolidinedione and biguanide), reducing urinal glucose reabsorption (e.g. gliflozins), and prolonging insulin sensitive [e.g. dipeptidyl peptidase 4 (DPP-4) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonists] [American Diabetes Association, 2019b]. These antidiabetic drugs help DM patients to maintain their blood glucose levels with various adverse effects (Table 1) , such as urine-tract infection, lactoacidosis, hypoglycemia, and obesity. These drug-related adverse effects can deteriorate the quality of life of DM patients and create unsurmountable difficulties for proper dosing regimens in a clinical setting. It has been observed that DPP-4 inhibitors can exert a similar efficacy in reducing blood glucose levels without severe adverse effects such as hypoglycemia as compared with sulfonylurea. 6 Nevertheless, The perceptions of natural compounds against dipeptidyl peptidase 4 in diabetes: from in silico to in vivo various adverse side effects associated with the current DPP-4 inhibitor can still be observed that, in turn, can severely limit their practical application. As such, there is a clinical demand for novel DPP-4 inhibitors from various sources including chemical synthesis and botanic sources containing herbs and plants with fewer side effects. In this article, we have reviewed various approaches including in silico, in vitro enzymatic and cell assays, and in vivo animal tests in the search for natural DPP-4 inhibitors for the treatment of type 2 diabetes. Two forms of DPP-4 DPP-4, which is a 88 kDa serine protease, contains one region of cytoplasmic region (amino acids 1-6) coupled with transmembrane domain (amino acids 7-28) and extracellular region (amino acids 29-766) with the main catalytic domain. 14 There are two DPP-4 isoforms in the body: membranebound DPP-4 (mDPP-4) composed of full-length DPP-4 peptide; and soluble DPP-4 (sDPP-4), whose cytoplasmic and transmembrane regions are absent. 14 Both forms can exert various biological activities in regulation of physiology and pathology. 15 Biological function of soluble form DPP-4 sDPP-4 is secreted by lymphocytes, circulates in the blood, 16 and shows high concentration in kidney. 17 It has been observed that sDPP-4 plays various roles in improving skeleton muscle activity, immunocyte activation, chemotaxis, and homeostasis. sDPP-4 can secrete into serum via the response of skeletal muscle cells upon acute physical activities or feeding protein hydrolysate. 18 Secreted sDPP-4 can reduce vasoconstriction that is caused by neuropeptide Y (NPY) and subsequently increase the arteriolar diameter of skeletal muscle that provides a physiological explanation for raising training efficiency caused by 20 In addition to arteriolar diameter of skeletal muscle, secreted sDPP-4 acts as myokine, which stimulates inflammation in smooth muscles from blood vessel through activating protease-activated receptor 2 (PAR2)/ERK/NF-κB signaling pathway, increasing proinflammatory cytokine release and finally stimulating smooth muscle cell proliferation. 21 In T-cell activation, sDPP-4 can activate T-cell proliferation via co-stimulation with T-cell receptor (TCR) signaling and Toll-like receptor, whose activation is neither associated with its enzymatic activity nor with adenosine deaminase binding. 25-28 On the other hand, sDPP-4 can upregulate the expressions of IL-6 and TNF-α in monocyte through caveolin-1/ERK/NF-κB/c-Fos signaling, which is involved in monocyte proliferation. 29 It is noteworthy that Tansi et al. proved the interaction between DPP-4 and HIV-1 transcription regulator Tat (HIV-1-Tat). 30 Markedably, the effect on DPP-4/HIV-1-Tat in viral infection and proliferation needs further investigative attention. The role of sDPP-4 in chemotaxis regulation is related to the degradation of chemokine. Hematopoietic stem cell homing is attracted by stromal cell-derived factor 1 (SDF-1/CXCL12) and colony-stimulating factors (CSFs), which are substrates of both sDPP-4 and mDPP4. 15, 31 Accordingly, sDPP-4 inhibition can improve success rate of transplantation after analyzing the relationship between sDPP-4 activity and hematopoietic stem cell transplantation. 32 The known DPP-4 (both soluble and membrane-bound forms) substrates include numerous homeostatic hormones such as GLP-1, NPY, glucagon, peptide Y, and secretin, which accurately regulate blood sugar homeostasis. 15 GLP-1 is involved in insulin sensitivity and secretion, food reward, and appetite through ghrelin and leptin, and cellular metabolism with adiponectin. 15 activity in end-stage renal disease patients before and after kidney transplantation, and sDPP-4 activities were found to decrease after kidney transplantation. 50 These results suggest that serum sDPP-4 activity can be a potential biomarker for monitoring the progress of autoimmune disease and the prognosis of organ transplantation. Interestingly, serum sDPP-4 activity can be associated with the progress of chronic obstructive pulmonary disease (COPD), 51 which is highly correlated with respiratory inflammation, obviously indicating the relationship between serum sDPP-4 activity and COPD progression. 52 However, the prognosis of malignant pleural mesothelioma (MPM), which is a rare pulmonary malignancy, can be predicted by sDPP-4 activity in pleural fluid. 53 The pathological correlation between sDPP-4 activity and MPM prognosis is still veiled. These reports provide interesting suggestions about sDPP-4 levels as the biomarkers of various diseases, which are not easy to monitor in serum or other body fluid. Remarkably, mDPP-4 can be found mainly in the kidney, gastrointestinal tract, T lymphocytes, and reproductive organs. 54, 55 Biological activities of mDPP-4 include the regulation of immune response and blood vessel function. 15 mDPP4, also named CD26, is a T-cell co-stimulator of T-cell receptor responding to antigen-presenting cells. 56 Thus, mDPP-4 recently has been 4 journals.sagepub.com/home/taj considered as a potent target in treatment of transplantation and autoimmune disease. Dolanbay et al. reported an interesting study about the impact of mDPP-4 inhibition in early pregnancy that can be important in treating recurrent implantation failure. 57 In hematopoietic stem cell transplantation, graft-versus-host disease (GVHD) is a common complication, which is critical in survival rate after transplantation. 58 Zhang et al. proved the association between Th17 cells and GVHD and which Th17 cell can be regulated by mDPP-4 inhibition that indicates current DPP-4 inhibitors can help ameliorating the onset of GVHD. 59 The impact of mDPP-4 in immune regulation is also implicated in autoimmune disease and hypersensitivity. mDPP-4 expression levels in CD8 + T cells of Hashimoto's thyroiditis patients are significantly lower than healthy subjects that is plausibly attributed to disease progression. 60 In contrast, mDPP-4 levels are almost 11-fold higher in psoriatic skin than in normal skin, asserting the involvement of mDPP-4 in psoriatic development. 61 mDPP-4 plays a positive role in asthma progress through promoting T-cell activation. 62 These reports have unequivocally demonstrated the positive role played by mDPP-4 in immune regulation. mDPP-4 acts on both endothelial and epithelial cells in regulation of blood vessel function,. In addition to endothelial inflammation caused by sDPP-4, the role of mDPP-4 in endothelial generally involves the endothelial migration, angiogenesis, and proliferation under hypoxia status, which can be found in the development of endometriosis. 63 Xu et al. have pointed out that DPP-4 inhibitors that can alleviate pulmonary artery remodeling and, finally, delay the development of pulmonary hypertension. 64 In the regulation of cardiovascular function, mDPP-4 inhibition can reverse diastolic left ventricular dysfunction via inhibiting mDPP-4/SDF-1α related angiogenesis. 65 mDPP-4 involves in epithelial-mesenchymal transition (EMT) for epithelial cell, 66 suggesting the potential implication of mDDP-4 in promoting cancer development. In fact, breast cancer metastasis can be triggered by DPP4 inhibition through CXCL12/CXCR4/mTOR pathway. 67 However, DPP-4 inhibitor shows the opposite activity in non-small cell lung cancer, which suppresses cancer cell growth via macrophagemediated natural killer (NK) cell activation. 68 Collectively, these studies have furnished comprehensive descriptions of mDPP-4 biological functions in the whole body and further manifest that DPP-4 inhibition (sDPP-4 or mDPP-4) can produce unexpected side effects. The endocrinological impact of DPP-4 is more prominent in the mediation of blood glucose. DPP-4 inhibition is a predominant approach for treating diabetes because of prolonged incretin half-lives within serum, especially in type 2 DM. 69 In addition, it has been suggested that sitagliptin can preserve pancreatic β-cell function and subsequently stabilize insulin secretion as shown by two 4-year clinical trials, in which sitagliptin was adopted to treat slowly progressive type 1 DM (SPTIDDM) and latent autoimmune diabetes adult (LADA). 55, 70 In addition to clinical treatment, DPP-4 levels can be used as a biomarker. For instance, high serum sDPP-4 levels can be referred to the elevated glycation end products, which subsequently evoke endothelial cell damage and diabetic nephropathy incidence. 71, 72 In addition, high serum sDPP-4 levels also indicate worse drug response to DPP-4 inhibitor and hyperglycemia, which are the indicators of poor glycemic control and advanced disease progress. 73, 74 The above information emphasizes the effect of DPP-4 inhibition and monitoring in DM treatment. The method of screening DPP-4 inhibitor and the recent known natural DPP-4 inhibitors are presented in the following. In silico screening of DPP-4 inhibitors Virtual screening has been seamlessly integrated into drug discovery and development 75 and its success significantly relies on compound library, 76 especially the structural diversity of compound library. 77 For instance, microalgal metabolites were screened for DDP-4 inhibitors. 78 Compared with the synthesized chemicals, natural compound libraries generally consist of more structurally diverse compounds than their synthetic counterparts, 79 providing a better screening resource. As such, numerous studies have adopted various natural compound libraries to find novel DDP-4 inhibitors as listed in Table 2 . It is not uncommon to observe that docking studies were carried out based on a single DDP-4 crystal structure, despite the fact that a great number of DDP-4-inhibitor co-complex structures have been deposited in the Protein Data Bank (PDB). Deng et al. 88 for instance, docked a series of synthesized triazole-based uracil derivatives into the linagliptin-DDP4 co-complex structure (PDB code: 2RGU) using the standard precision (SP) Glide (Schrödinger, Inc.), which places internally generated ligand conformations with various positions and orientations into the binding pocket. Deng et al. 89 employed Gold (Cambridge Crystallographic Data Center), which is a genetic algorithm (GA)-based scheme to explore the conformational flexibility of ligand and the rotational flexibility of receptor, to dock synthesized pyrazolo inhibitors into the quinazolinone-DDP4 co-complex structure (PDB code: 2ONC). 90 It should be noted that both Glide and Gold are flexible docking algorithms. 91 Nevertheless, DDP-4 is unrestrained per se as manifested by the fact that DDP-4 consists of various binding subsites, namely S 1 , S' 1 , S 2 , S' 2 , and extensive S 2 , etc., to which the corresponding amino acids of the DDP4 substrate peptide designated by P 1 , P' 1 , P 2 , P' 2 , etc. from the nearest to the farthest cleavage point can bind as shown in Figure 1 ,92 and S 2 , which is composed of various hydrophobic residues, namely GLU205 and GLU206 dyad and ARG125, is highly plastic. 93 Furthermore, Nabeno et al. categorized inhibitors into three different classes (Figure 1 ) based on the interactions between inhibitor and DDP-4 subsites as listed in Table 3 , from which it can be observed that inhibitors of different classes bind to different DDP-4 subsites, and S 1 and S 2 are the Table 2 . Natural compound libraries adopted by various studies. Traditional Chinese Medicine Database (TCM Database@Taiwan) Chen 80 Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT) Mangal et al. 81 Natural Products subset of the ZINC database Irwin and Shoichet et al. 82 The Binding Database (BindingDB) Liu et al. 83 Antidiabetic natural compounds database (ADNCD) Khatoon et al. 84 Phenol-explorer Rothwell et al. 85 In-house natural products database (NPD) Zhang et al. 86 The NuBBE Database (NuBBEDB) Nguyen et al. 87 94 that, in turn, can be further noticeable the promiscuity of target protein. 95 As such, the promiscuity of DDP-4 cannot be fully taken into account unless more sophisticated structure-based ensemble docking schemes such as SVM-Pose/SVM-Score combinatorial ensemble docking 96 or analog-based pharmacophore ensemble schemes such as pharmacophore ensemble/support vector machine 97 can be adopted. It can be argued that molecular dynamics (MD) can be used to address the flexibility of DDP4 as illustrated by the study of Liu et al. 98 Nevertheless, the lengthy MD calculation will substantially increase computational time and expense, making it impractical to be carried out in a high-throughput fashion, let alone the more resource-demanded quantum mechanical (QM)/ molecular mechanics (MM) algorithm. 99 There are four types of assay methods for screening DPP-4 inhibitors for direct testing: direct enzymatic assay, in vitro cell assay, ex vivo assay, and in vivo animal tests. DPP-4 and tested compounds are mixed in the direct enzymatic assay, followed by adding specific substrate peptides such as glypro-p-nitroanilide. The chemical p-nitroanilide will be released from peptides and the amount is determined by optical absorption at 405 nm at noninhibition state. 105 This method is fast for analysis and can be used to evaluate the inhibition pattern from calculated K i values. However, the minimum changes within direct enzymatic assay cannot be directly translated into the actual bioactivity in cells and animals. 106 Ex vivo assay can simulate the biological interaction within body, whereas it needs fresh serum or tissue sample as the source of DPP-4. 107,108 Moreover, previous studies reported that mucosal DPP-4 inhibition can be possibly related to the onset of coeliac disease, which is an autoimmune disorder due to the immune response to gluten. 109, 110 However, a modern version of DPP4 activity assay needs to homogenize the whole intestinal biopsy that, in turn, can lead to mucosal DPP-4 inhibition. 108 Yazbeck et al. have derived a new DPP4 substrate with 13 C isotope that can be released upon reaction with DPP-4. 111 As such, the requirement to homogenize the biopsy is completely exonerated, leading to higher correlation as compared with its conventional counterparts. 111 Myocytes and pancreatic cells are often used in the cell-based assays to discover DPP-4 inhibitors. Because β-cells in pancreatic islet is an important GLP-1 target, the downstream signaling of GLP-1 in pancreatic cells can be an indicator or biomarker of DPP-4 activity. 112 In addition, GLP-1 attenuates lipopolysaccharide (LPS)-induced cardiomyocyte inflammation. The variations of inflammatory signaling including NF-κB, ERK, and TNF-α within LPS-induced cardiomyocyte can indirectly gauge DPP-4 activity. 113 Nevertheless, the results of cell-based assay can be an authentic representative of the realistic situation mainly due to the fact that they do not consider in vivo pharmacodynamic and pharmacokinetic factors. Nevertheless, direct action upon target cells can be very helpful in detailing intracellular dynamics prior to clinical or animal tests. DPP-4 inhibitors have been highlighted as potential regimen for autoimmune-disease based on the characteristics in T-cell activation and inflammation. 55 Notably, autoimmune animal model becomes a platform for testing in vivo efficacy of DPP-4 inhibitors in long-term administration. 114 Alternatively, in vivo assay of DPP-4 inhibitory efficacy can be verified by diabetic animal model despite the fact that DPP-4 can degrade GLP-1, leading to insulin desensitization and secretion decrease. 112 The most unvanquished limitation of in vivo test is that only end-point effect can be observed in pre-testing drug candidate despite the fact that it is more related to clinical situations. The data retrieved from in vitro and direct enzymatic assay can be synergistically essential for understanding the conceivable hypoglycemic mechanism. The effects of DPP-4 studies were mainly focused on immune, endocrine, and neuron system from the end of 1990s to early of 2000s. [115] [116] [117] A study reported in 2006 that incretin was the molecular target of DPP-4, suggesting the implication of DPP-4 inhibitor in diabetes treatment. Consequently, the diabetic research has turned into a new paradigm for searching for antidiabetic DPP-4 inhibitors. 118 To date, only very limited natural DPP-4 inhibitors from various sources/origins have been reported (Table 4 ). Natural DPP-4 inhibitors from different origins using different approaches for screening the compound to reach the target are summarized as follows. In addition to plant source, DPP-4 inhibitors from animals and microbes are singlesubclasses, in which DPP-4 inhibitors from animals and microbes are peptides and macrolides, respectively. Interestingly, the most predominant subclasses of DPP-4 inhibitors are terpenoids, peptides, phenolics, and flavonoids. 121 The protein hydrolysates from whey, barbel, and yam can reduce the DPP-4 activity in enzymatic measurements. [122] [123] [124] [125] Through partition by molecular sieve, the highest inhibition peptide sequences of DPP-4 such as Ala-Pro, Leu-Pro-Val-Pro-Gln, Trp-Ser-Gly, and Phe-Ser-Asp have been found. [126] [127] [128] Nevertheless, these results from in vitro enzymatic assays cannot guarantee a promising future since physiological regulation of DPP-4 is far more complicated than bench-top experiments. Therefore, the results from direct enzymatic assay for new candidates or hits require further validation such as in vivo investigations to confirm their actual therapeutic values when compared with clinical medicines. Previous sections have described the biological functions, assay methods, and known natural DPP-4 inhibitors, which are purported to treat DM. However, DPP-4 inhibition can possibly cause unexpected sequela owing to its entanglement with immune response and endothelial functions. In fact, the roles of DPP-4 in tumorigenesis and progression, respectively, have been reviewed recently. 144, 145 In lung cancer and 153 In conclusion, DPP-4 inhibitors can be used to treat DM, whereas their complications with other immune disease or cancer should be seriously considered. The effect of virtual screening via computational biology or informatics further combined with in vitro enzymatic and cell assay, and in vivo animal tests offer a promising approach to discover candidates or hits for expediting the preclinical development process ( Figure 3 ). Nevertheless, poor or ill drug absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties make substantial contributions to drug attritions, 154 and little effort has been dedicated to profiling ADME/Tox properties of DDP-4 inhibitors. As such, it is necessary to predict ADME/ Tox parameters in the process of virtual screening, which should be carried by adopting schemes that can consider the unstructured nature of DDP-4, to minimize the late-stage failures. The author(s) received no financial support for the research, authorship, and/or publication of this article. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045 The how-to for type 2: an overview of diagnosis and management of type 2 diabetes mellitus Recent advances in the pathogenesis of microvascular complications in diabetes Lifestyle management: standards of medical care in diabetes-2019 Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019 The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type 2 diabetes: accumulated evidence from randomised controlled trial Progressing from metformin to sulfonylureas or meglitinides Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas Thiazolidinedione safety Comparative safety for cardiovascular outcomes of DPP-4 inhibitors versus glimepiride in patients with type 2 diabetes: a retrospective cohort study Metformin-associated lactic acidosis: current perspectives on causes and risk Alpha-glucosidase inhibitors and hepatotoxicity in type 2 diabetes: a systematic review and meta-analysis Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4 Decreased soluble dipeptidyl peptidase IV activity as a potential serum biomarker for COPD COPD as a disease of immunosenescence Clinical significance of soluble CD26 in malignant pleural mesothelioma Proteomics. Tissue-based map of the human proteome Dipeptidyl peptidase-4(DPP-4) inhibitors: promising new agents for autoimmune diabetes Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function Expression of trophinin and dipeptidyl peptidase IV in endometrial co-culture in the presence of an embryo: a comparative immunocytochemical study Effects of AGVHD and CGVHD on survival rate in patients with acute myeloid leukemia after allogeneic stem cell transplantation Cellular and molecular mechanisms in graft-versus-host disease CD26 expression is down-regulated on CD8 + T cells in patients with hashimoto's thyroiditis CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes CD26 and asthma: a comprehensive review CD26/ DPPIV down-regulation in endometrial stromal cell migration in endometriosis Dipeptidyl peptidase IV (DPP-4) inhibition alleviates pulmonary arterial remodeling in experimental pulmonary hypertension Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions Hibiscus sabdariffa polyphenols alleviate insulin resistance and renal epithelial to mesenchymal transition: a novel action mechanism mediated by type 4 dipeptidyl peptidase Inhibition of dipeptidyl peptidase-4 accelerates epithelial-mesenchymal transition and breast cancer metastasis via the CXCL12/ CXCR4/mTOR axis The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity The effects of novel antidiabetic drugs on albuminuria in type 2 diabetes mellitus: a systematic review and metaanalysis of randomized controlled trials Possible long-term efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for slowly progressive type 1 diabetes (SPIDDM) in the stage of non-insulin-dependency: an open-label randomized controlled pilot trial (SPAN-S) Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulinlike growth factor II receptor Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of diabetic nephropathy in Chinese patients with newly diagnosed type 2 diabetes: a cross-sectional study Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea The serum level of soluble CD26/dipeptidyl peptidase 4 increases in response to acute hyperglycemia after an oral glucose load in healthy subjects: association with high-molecular weight adiponectin and hepatic enzymes Integration of virtual and physical screening Drug discovery: a question of library design Advances in virtual screening Computational screening of dipeptidyl peptidase IV inhibitors from micoroalgal metabolites by pharmacophore modeling and molecular docking Natural products in drug discovery TCM Database@Taiwan: the world's largest traditional Chinese medicine database for drug screening in silico NPACT: naturally occurring plant-based anti-cancer compound-activity-target database Zinc-a free database of commercially available compounds for virtual screening BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities ADNCD: a compendious database on anti-diabetic natural compounds focusing on mechanism of action Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach Novel alginate-based nanocarriers as a strategy to include high concentrations of hydrophobic compounds in hydrogels for topical application Discovery of triazole-based uracil derivatives bearing amide moieties as novel dipeptidyl peptidase-IV inhibitors Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV Software for molecular docking: a review A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII Unique binding mode of evogliptin with human dipeptidyl peptidase IV A comprehensive survey of small-molecule binding pockets in proteins Prediction of N-methyl-D-aspartate receptor GluN1-ligand binding affinity by a novel SVM-pose/SVMscore combinatorial ensemble docking scheme A novel approach using pharmacophore ensemble/support vector machine (PHE/SVM) for prediction of hERG liability Establishment of a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins A method of combined quantum mechanical (Qm)/molecular mechanics (Mm) treatment of large polyatomic systems with charge transfer between the Qm and Mm Fragments Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV 8-(3-(R)-aminopiperidin-1-Yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylme thyl)-3,7-dihydropurine-2,6-dione (Bi 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes ,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Discovery and preclinical profile of teneligliptin (3-[(2s,4s)-4-[4-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl] thiazolidine): a highly potent, selective, longlasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes Investigating the contributions of residues to dipeptidyl peptidase-IV inhibitor binding by molecular dynamics simulation Designing screens: how to make your hits a hit Novel potentials of the DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in rat ex-vivo heart model Soybeanand lupin-derived peptides inhibit DPP-IV activity on in situ human intestinal caco-2 cells and ex vivo human serum Serum and intestinal dipeptidyl peptidase IV (DPP IV/ CD26) activity in children with celiac disease Coeliac disease Development of a (13)C stable isotope assay for dipeptidyl peptidase-4 enzyme activity a new breath test for dipeptidyl peptidase activity DPP4 in diabetes Sitagliptin attenuates inflammatory responses in lipopolysaccharidestimulated cardiomyocytes via nuclear factor-kB A methodological review of induced animal models of autoimmune diseases IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient dark agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions CD26/ dipeptidyl peptidase 4-deficiency alters thymic emigration patterns and leukcocyte subsets in F344-rats age-dependently The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes Exploration of natural enzyme inhibitors with hypoglycemic potentials amongst eucalyptus Spp. by in vitro assays Chemometrics optimized extraction procedures, phytosynergistic blending and in vitro screening of natural enzyme inhibitors amongst leaves of Tulsi, Banyan and Jamun Anti-diabetic effect of a traditional Chinese medicine formula Inhibition of dipeptidyl peptidase (DPP)-IV and αglucosidase activities by pepsin-treated whey proteins The evaluation of dipeptidyl peptidase (DPP)-IV, αglucosidase and angiotensin converting enzyme (ACE) inhibitory activities of whey proteins hydrolyzed with serine protease isolated from Asian pumpkin (Cucurbita ficifolia) Effects of yam dioscorin interventions on improvements of the metabolic syndrome in high-fat diet-induced obese rats Recovery, viscoelastic and functional properties of Barbel skin gelatine: investigation of anti-DPP-IV and anti-prolyl endopeptidase activities of generated gelatine polypeptides Structure activity relationship modelling of milk proteinderived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity Purification, identification and structural modelling of DPP-IV inhibiting peptides from barbel protein hydrolysate Purification, identification and molecular mechanism of two dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from Antarctic krill (Euphausia superba) protein hydrolysate Ephedrine as a lead compound for the development of new DPP-IV inhibitors Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine Calebin A: analytical development for pharmacokinetics study, elucidation of pharmacological activities and content analysis of natural health products Structure(-) activity relationship and molecular docking of natural product library reveal chrysin as a novel dipeptidyl peptidase-4 (DPP-4) inhibitor: an integrated in silico and in vitro study PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L Acute assessment of an aspalathin-enriched green rooibos (Aspalathus linearis) extract with hypoglycemic potential Cyanogenetic glycosides and simple glycosides from the linseed meal Screening of a natural compound library identifies emodin, a natural compound from Rheum palmatum Linn that inhibits DPP4 Screening and identification of DPP-4 inhibitors from Xiaokean formula by a fluorescent probe Anti-αglucosidase and anti-dipeptidyl peptidase-IV activities of extracts and purified compounds from vitis thunbergii var. Taiwaniana Phenolic glycosides and other constituents from the bark of Magnolia officinalis Plants Fagonia cretica L. and Hedera nepalensis K. Koch contain natural compounds with potent dipeptidyl peptidase-4 (DPP-4) inhibitory activity Polyalthia clerodane diterpene potentiates hypoglycemia via inhibition of dipeptidyl peptidase 4 Natural dipeptidyl peptidase-IV inhibitor mangiferin mitigates diabetes-and metabolic syndrome-induced changes in experimental rats Grassypeptolides as natural inhibitors of dipeptidyl peptidase 8 and T-cell activation Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: a systematic review and meta-analysis Critical role of dipeptidyl peptidase IV: a therapeutic target for diabetes and cancer Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: a Surveillance Epidemiology and Endpoint Research Medicare study DPPIV promotes endometrial carcinoma cell proliferation, invasion and tumorigenesis Downregulation of dipeptidyl peptidase 4 accelerates progression to castration-resistant prostate cancer Drug fever and acute inflammation from hypercytokinemia triggered by dipeptidyl peptidase-4 inhibitor vildagliptin Short-term dipeptidyl peptidase-4 inhibitor use increases the risk of herpes zoster infection in Asian patients with diabetes Chinese Society of Gastroenterology and Chinese Medical Association. Evidence-based consensus on opportunistic infections in inflammatory bowel disease (republication) Immunological pathogenesis of inflammatory bowel disease Dipeptidyl peptidase-4 inhibitors and inflammatory bowel disease risk: a meta-analysis ADMET in silico modelling: towards prediction paradise?