Modeling Compound-Target Interaction Network of Traditional Chinese Medicines for Type II Diabetes Mellitus: Insight for Polypharmacology and Drug Design

In this study, in order to elucidate the action mechanism of traditional Chinese medicines (TCMs) that exhibit clinical efficacy for type II diabetes mellitus (T2DM), an integrated protocol that combines molecular docking and pharmacophore mapping was employed to find the potential inhibitors from TCM for the T2DM-related targets and establish the compound-target interaction network. First, the prediction capabilities of molecular docking and pharmacophore mapping to distinguish inhibitors from noninhibitors for the selected T2DM-related targets were evaluated. The results show that molecular docking or pharmacophore mapping can give satisfactory predictions for most targets but the validations are still quite necessary because the prediction accuracies of these two methods are variable across different targets. Then, the Bayesian classifiers by integrating the predictions from molecular docking and pharmacophore mapping were developed, and the well-validated Bayesian classifiers for 15 targets were utilized to find the potential inhibitors from TCM and establish the compound-target interaction network. The analysis of the compound-target network demonstrates that a small portion (18.6%) of the predicted inhibitors can interact with multitargets. The pharmacological activities for some potential inhibitors have been experimentally confirmed, highlighting the reliability of the Bayesian classifiers. Besides, it is interesting to find that a considerable number of the predicted multitarget inhibitors have free radical scavenging/antioxidant activities, which are closely related to T2DM. It appears that the pharmacological effect of the TCM formulas is determined not only by the compounds that interact directly with one or more T2DM-related targets, but also by the compounds with other supplementary bioactivities important for relieving T2DM, such as free radical scavenging/antioxidant effects. The mechanism uncovered by this study may offer a deep insight for understanding the theory of the classical TCM formulas for combating T2DM. Moreover, the predicted inhibitors for the T2DM-related targets may provide a good source to find new lead compounds against T2DM.

[1]  Da Yeon Lee,et al.  New estrogenic compounds isolated from Broussonetia kazinoki. , 2010, Bioorganic & medicinal chemistry letters.

[2]  Daniela Schuster,et al.  Identification of bioactive natural products by pharmacophore-based virtual screening. , 2010, Current pharmaceutical design.

[3]  Ronald W. Davis,et al.  Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. , 1999, Science.

[4]  Hong-yu Zhang,et al.  Natural products and drug discovery , 2009, EMBO reports.

[5]  Yongbo Hu,et al.  Comparison of Several Molecular Docking Programs: Pose Prediction and Virtual Screening Accuracy , 2009, J. Chem. Inf. Model..

[6]  D. Moller,et al.  New drug targets for type 2 diabetes and the metabolic syndrome , 2001, Nature.

[7]  Maria Greabu,et al.  Free radical activity in obese patients with type 2 diabetes mellitus. , 2006, Romanian journal of internal medicine = Revue roumaine de medecine interne.

[8]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[9]  N. Hotta,et al.  Lipid peroxide level in plasma of diabetic patients. , 1979, Biochemical medicine.

[10]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[11]  R. Friesner,et al.  Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides† , 2001 .

[12]  H. Kitano.  Towards a theory of biological robustness , 2007, Molecular systems biology.

[13]  Tingjun Hou,et al.  A 3D Structure Database of Components from Chinese Traditional Medicinal Herbs , 2002, J. Chem. Inf. Comput. Sci..

[14]  Dennis M. Krüger,et al.  Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors , 2010, ChemMedChem.

[15]  M. DePamphilis,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[16]  Youyong Li,et al.  ADMET evaluation in drug discovery. 12. Development of binary classification models for prediction of hERG potassium channel blockage. , 2012, Molecular pharmaceutics.

[17]  Willem Dhooge,et al.  Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta. , 2006, Journal of medicinal chemistry.

[18]  Alan L Harvey,et al.  Current strategies for drug discovery through natural products , 2010, Expert opinion on drug discovery.

[19]  G. Reaven,et al.  Pathophysiology of insulin resistance in human disease. , 1995, Physiological reviews.

[20]  Mengyue Wang,et al.  Antioxidant Phenolic Compounds from the Stems of Entada phaseoloides , 2012, Chemistry & biodiversity.

[21]  Ying Zhang,et al.  Three new isoflavone glycosides from Tongmai granules , 2011, Journal of Asian natural products research.

[22]  H. Shimoda,et al.  Phytoestrogens from the roots of Polygonum cuspidatum (Polygonaceae): structure-requirement of hydroxyanthraquinones for estrogenic activity. , 2001, Bioorganic & medicinal chemistry letters.

[23]  D. Greene,et al.  Acute and chronic complications of diabetes mellitus in older patients. , 1986, The American journal of medicine.

[24]  Tingjun Hou,et al.  Drug-likeness analysis of traditional Chinese medicines: prediction of drug-likeness using machine learning approaches. , 2012, Molecular pharmaceutics.

[25]  Siu Cheung Hui,et al.  Computational methods for Traditional Chinese Medicine: A survey , 2007, Comput. Methods Programs Biomed..

[26]  Simon Smyth,et al.  Diabetes and obesity: the twin epidemics , 2006, Nature Medicine.

[27]  Xin Wen,et al.  BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities , 2006, Nucleic Acids Res..

[28]  S. Wild,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[29]  Didier Rognan,et al.  Protein-Ligand-Based Pharmacophores: Generation and Utility Assessment in Computational Ligand Profiling , 2012, J. Chem. Inf. Model..

[30]  Kuan-Chung Chen,et al.  Traditional Chinese medicine, a solution for reducing dual stroke risk factors at once? , 2011, Molecular bioSystems.

[31]  Shuang-Cheng Ma,et al.  Antioxidative glycosides from the leaves of Ligustrum robustum. , 2003, Journal of natural products.

[32]  M. Melzig,et al.  Effect of different phenolic compounds on alpha-amylase activity: screening by microplate-reader based kinetic assay. , 2005, Die Pharmazie.

[33]  Zhihai Liu,et al.  Comparative Assessment of Scoring Functions on a Diverse Test Set , 2009, J. Chem. Inf. Model..

[34]  Robert C. Glen,et al.  Winnow based identification of potent hERG inhibitors in silico: comparative assessment on different datasets , 2012, Journal of Cheminformatics.

[35]  Tingjun Hou,et al.  Recent development and application of virtual screening in drug discovery: an overview. , 2004, Current pharmaceutical design.

[36]  Calvin Yu-Chian Chen,et al.  In Silico Investigation of Potential Src Kinase Ligands from Traditional Chinese Medicine , 2012, PloS one.

[37]  S. Srivastava,et al.  Prevention of Sugar-Induced Cataractogenesis in Rats by Butylated Hydroxytoluene , 1988, Diabetes.

[38]  Lin He,et al.  Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study , 2011, PLoS Comput. Biol..

[39]  Masayuki Yoshikawa,et al.  Bioactive constituents from Chinese natural medicines. XV. Inhibitory effect on aldose reductase and structures of Saussureosides A and B from Saussurea medusa. , 2005, Chemical & pharmaceutical bulletin.

[40]  M J Crabbe,et al.  Low apparent aldose reductase activity produced by monosaccharide autoxidation. , 1985, The Biochemical journal.

[41]  Junmei Wang,et al.  Structure – ADME relationship : still a long way to go ? , 2008 .

[42]  Evan Bolton,et al.  PubChem3D: conformer ensemble accuracy , 2013, Journal of Cheminformatics.

[43]  T. Ferris,et al.  Oxygen free radicals in ischemic acute renal failure in the rat. , 1984, The Journal of clinical investigation.

[44]  Johannes Novak,et al.  Oregano: a source for peroxisome proliferator-activated receptor gamma antagonists. , 2008, Journal of agricultural and food chemistry.

[45]  Qian Li,et al.  Drug-likeness analysis of traditional Chinese medicines: 1. property distributions of drug-like compounds, non-drug-like compounds and natural compounds from traditional Chinese medicines , 2012, Journal of Cheminformatics.

[46]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[47]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[48]  V. R. Khairullina,et al.  Comparative study of the antioxidant properties of selected flavonols and flavanones , 2010 .

[49]  Yu Zhang,et al.  Three New Polyyne (= Polyacetylene) Glucosides from the Edible Roots of Codonopsis cordifolioidea , 2008 .

[50]  Lei Chen,et al.  Drug-likeness analysis of traditional Chinese medicines: 2. Characterization of scaffold architectures for drug-like compounds, non-drug-like compounds, and natural compounds from traditional Chinese medicines , 2013, Journal of Cheminformatics.

[51]  Da Yeon Lee,et al.  New Estrogenic Compounds Isolated from Broussonetia kazinoki. , 2010 .

[52]  Jiabo Li,et al.  New features that improve the pharmacophore tools from Accelrys. , 2011, Current computer-aided drug design.

[53]  N. Morral,et al.  Novel targets and therapeutic strategies for type 2 diabetes , 2003, Trends in Endocrinology & Metabolism.

[54]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[55]  D J Newman,et al.  The influence of natural products upon drug discovery. , 2000, Natural product reports.

[56]  Masayuki Yoshikawa,et al.  Structural requirements of flavonoids and related compounds for aldose reductase inhibitory activity. , 2002, Chemical & pharmaceutical bulletin.

[57]  G. Bemis,et al.  The properties of known drugs. 1. Molecular frameworks. , 1996, Journal of medicinal chemistry.

[58]  D L McGee,et al.  Diabetes and Cardiovascular Risk Factors: The Framingham Study , 1979, Circulation.

[59]  Dexin Kong,et al.  Inhibitory Activity of Flavonoids against Class I Phosphatidylinositol 3-Kinase Isoforms , 2011, Molecules.

[60]  A. Marcus,et al.  Safety of drugs commonly used to treat hypertension, dyslipidemia, and Type 2 diabetes (the metabolic syndrome): part 2. , 2000, Diabetes technology & therapeutics.

[61]  Masayuki Yoshikawa,et al.  Bioactive constituents from chinese natural medicines. XXXVI. Four new acylated phenylethanoid oligoglycosides, kankanosides J1, J2, K1, and K2, from stems of Cistanche tubulosa. , 2010, Chemical & pharmaceutical bulletin.

[62]  James G. Nourse,et al.  Reoptimization of MDL Keys for Use in Drug Discovery , 2002, J. Chem. Inf. Comput. Sci..

[63]  R. Brinton,et al.  Structure-based virtual screening for plant-based ERbeta-selective ligands as potential preventative therapy against age-related neurodegenerative diseases. , 2005, Journal of medicinal chemistry.

[64]  F. Pasquier,et al.  Diabetes and cognitive impairment: how to evaluate the cognitive status? , 2010, Diabetes & metabolism.

[65]  Choong Yong Ung,et al.  Can an in silico Drug‐Target Search Method Be Used to Probe Potential Mechanism of Medicinal Plant Ingredients? , 2003 .

[66]  Yang Song,et al.  Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery , 2011, Nucleic Acids Res..

[67]  Lei Chen,et al.  ADME evaluation in drug discovery. 10. Predictions of P-glycoprotein inhibitors using recursive partitioning and naive Bayesian classification techniques. , 2011, Molecular pharmaceutics.

[68]  Calvin Yu-Chian Chen,et al.  TCM Database@Taiwan: The World's Largest Traditional Chinese Medicine Database for Drug Screening In Silico , 2011, PloS one.

[69]  Q Xie,et al.  Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. , 2001, Chemical research in toxicology.

[70]  H. Kitano.  A robustness-based approach to systems-oriented drug design , 2007, Nature Reviews Drug Discovery.

[71]  M. Tyers,et al.  Osprey: a network visualization system , 2003, Genome Biology.

[72]  Calvin Yu-Chian Chen,et al.  Mechanism of BAG1 repair on Parkinson’s disease-linked DJ1 mutation , 2012, Journal of biomolecular structure & dynamics.

[73]  David S. Wishart,et al.  DrugBank: a knowledgebase for drugs, drug actions and drug targets , 2007, Nucleic Acids Res..

[74]  Masayuki Yoshikawa,et al.  Bioactive Constituents from Chinese Natural Medicines. Part 15. Inhibitory Effect on Aldose Reductase and Structures of Saussureosides A and B from Saussurea medusa , 2006 .

[75]  Karin Kraft,et al.  [Type-2 diabetes]. , 2010, MMW Fortschritte der Medizin.

[76]  Ryan P. Million,et al.  Tapping the potential of fixed-dose combinations , 2007, Nature Reviews Drug Discovery.

[77]  Su-Sen Chang,et al.  Han ethnicity-specific type 2 diabetic treatment from traditional Chinese medicine? , 2013, Journal of biomolecular structure & dynamics.

[78]  Ravi Iyengar,et al.  Network analyses in systems pharmacology , 2009, Bioinform..

[79]  M. Peppelenbosch,et al.  Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives. , 2006, Biochimie.

[80]  Jin Sook Kim,et al.  Constituents of the flowers of Platycodon grandiflorum with inhibitory activity on advanced glycation end products and rat lens aldose reductase in vitro , 2010, Archives of pharmacal research.

[81]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[82]  B. Roth,et al.  Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia , 2004, Nature Reviews Drug Discovery.

[83]  Su-Sen Chang,et al.  Drug Design for Neuropathic Pain Regulation from Traditional Chinese Medicine , 2013, Scientific Reports.

[84]  Anton J. Hopfinger,et al.  Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships , 1994, J. Chem. Inf. Comput. Sci..

[85]  M. Small,et al.  Free Radical Activity in Type 2 Diabetes , 1990, Diabetic medicine : a journal of the British Diabetic Association.

[86]  Willem Dhooge,et al.  Subtle Side-Chain Modifications of the Hop Phytoestrogen 8-Prenylnaringenin Result in Distinct Agonist/Antagonist Activity Profiles for Estrogen Receptors α and β , 2006 .

[87]  D. Barlow,et al.  In silico search for multi-target anti-inflammatories in Chinese herbs and formulas. , 2010, Bioorganic & medicinal chemistry.

[88]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[89]  Peng Jiang,et al.  Molecular networks for the study of TCM Pharmacology , 2010, Briefings Bioinform..

[90]  A. Marcus,et al.  Safety of drugs commonly used to treat hypertension, dyslipidemia, and type 2 diabetes (the metabolic syndrome): part 1. , 2000, Diabetes technology & therapeutics.

[91]  Jin Sook Kim,et al.  Inhibitors of aldose reductase and formation of advanced glycation end-products in moutan cortex (Paeonia suffruticosa). , 2009, Journal of natural products.

[92]  R. Urban,et al.  Management of blood glucose in type 2 diabetes mellitus. , 2009, American family physician.

[93]  V. Chitra,et al.  Antidiabetic, Antioxidant and Antibacterial Activities of Leaf extracts of Adhatoda zeylanica. Medic (Acanthaceae) , 2009 .

[94]  Wendy Reiboldt,et al.  Resveratrol in raw and baked blueberries and bilberries. , 2003, Journal of agricultural and food chemistry.

[95]  Calvin Yu-Chian Chen,et al.  Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine , 2011, PLoS Comput. Biol..

[96]  N. de Kimpe,et al.  Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. , 2004, Journal of ethnopharmacology.

[97]  Tingjun Hou,et al.  ADME evaluation in drug discovery , 2002, Journal of molecular modeling.

[98]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[99]  Shun Xu,et al.  Drug-target network and polypharmacology studies of a Traditional Chinese Medicine for type II diabetes mellitus , 2011, Comput. Biol. Chem..

[100]  C. Nishimura,et al.  Alteration of lipid peroxide and endogenous antioxidant contents in retina of streptozotocin-induced diabetic rats: effect of vitamin A administration. , 1985, Japanese journal of pharmacology.

[101]  Su-Sen Chang,et al.  Two Birds with One Stone ? Possible Dual-Targeting H 1 N 1 Inhibitors from Traditional Chinese Medicine , 2011 .

[102]  Nan Wang,et al.  Two new flavonoid glycosides from the whole herbs of Hyssopus officinalis , 2010, Journal of Asian natural products research.