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Predicting Receptor Targets of Chinese Medicines

Explore TCM mechanisms, target prediction, bioinformatics modeling, and safety tests for novel therapeutic approaches using bioinformatics. Learn about standardization needs and molecular mechanisms for TCM database development.

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Predicting Receptor Targets of Chinese Medicines

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  1. Predicting Receptor targets of Traditional Chinese Medicines and Small Molecule TCM Database J. Jia and Y.Z. ChenDepartment of PharmacyNational University of SingaporeTel: 65-6616-6877; Email: phacyz@nus.edu.sg ; Web: http://bidd.nus.edu.sg • Content • TCM mechanism, targets, roles of bioinformatics and modeling • TCM and target databases • Target prediction by INVDOCK • Bioinformatics study of mechanism of interior warming herbs

  2. Therapeutics from Traditional Medicines • Potentially novel therapeutic approaches • Existing markets in certain countries and potential market in others • Need for standardization, validation, & further development • Markers for standardization • Molecular mechanism • Safety and efficacy tests • New recipes, combination drug mimics Pharmacology & Therapeutics 2000, 86:191-198

  3. Why receptor targets?Therapeutics from Traditional Medicines • Multiple herb therapies • Collective synergistic actions, maintenance and balance. • Mutual accentuation mutual enhancement mutual counteraction mutual suppression mutual antagonism mutual incompatibility • Multiple targets: • therapeutic effects • symptom treatment • toxicity modulation • Immune regulation • drug delivery • energy metabolism • harmonization Pharmacology & Therapeutics 2000, 86:191-198

  4. Computer Analysis of Molecular Mechanism of Traditional Medicine Therapeutic Target Therapeutic Target Database Herbal Ingredient Computer Match-Making Software  Traditional Medicine Database  Toxicity Target Drug Adverse Reaction Target Database  ADME protein Matched Targets Herbal Ingredient & Content Database  Drug Absorption Distribution Metabolism Excretion Database  Mutual Enhancement ? Mutual Counteraction ? Maintenance or Balance ? Delivery or Clearance ? • Collective therapeutic and maintenance effects • Toxicity / side effects and modulation • Drug delivery and clearance Y.Z. Chen and D.G. Zhi Proteins 2001;43: 217

  5. Medicinal Herb Databases at BIDD • TCM-ID: Traditional Chinese Medicine -Information Database  • Only database providing integrated and comprehensive info about: • TCM formula, constituent herbs, herbal ingredients, effect on proteins • Molecular structure • Function at the formula, herb and compound levels Function Structure Protein • Comparison with • existing TCM • databases: • Formula: • TCM-ID: 1000 • TCHFL: 270 • Herb: • TCM-ID: 1200 • TCSHL: 520 • TCMD: 1500 • Compound: • TCM-ID: 9000 • CNPD: 3000 • TCMD: 6800 Protein Compound Function Protein Herb Function Structure Protein Function Compound Protein Function Structure Protein TCM Formula Function Protein Compound Protein Herb TCHF Library Structure Function Protein Protein Compound TCSH Library TCMD CNPD

  6. INVDOCK Strategy for Match Making Science 1992;257: 1078 Proteins 1999; 36:1

  7. Chinese Natural Product Number of Identified Putative and Known Therapeutic Targets Number Confirmed or Implicated Therapeutic Targets by experiment Number of Identified Putative and Known Toxicity/Side effect Targets Number Confirmed or Implicated Toxicity/Side Effect Targets by experiment Acronycine 3 1 4 - Allicin 5 2 1 1 Baicalin 14 4 6 - Catechin 17 12 5 - Camptothecine 9 6 3 2 Dicoumarin 7 1 3 1 Emodin 6 3 5 1 Genistin 22 7 12 1 INVDOCK Test on Targets of Chinese Medicinal Herbal Ingredients(Am. J. Chin. Med. 2002, 30, 139)

  8. INVDOCK Test on TCM Target PredictionTherapeutic targets of Camptothecine(Am. J. Chin. Med. 2002, 30, 139)

  9. INVDOCK Test on TCM Target PredictionToxicity and side effect targets of Camptothecine(Am. J. Chin. Med. 2002, 30, 139)

  10. Exclusive ingredients Bioinformatics Study of Mechanism of TCM HerbsInterior Warming Herbs as an Example Chinese Medicinal Herbs Interior Warming Herbs All Other Herbs All ingredients of interior warming herbs All ingredients of the other herbs Interior warming effects primarily come from these ingredients COMPARE Exclusive ingredients Pharmacological effects possibly linked to interior warming Other Pharmacological and regulatory effects

  11. Pharmacological Effects Possibly Linked to Interior Warming

  12. Vasodilation and its Relation to Interior Warming • Why vasodiation produces warming effect or sensation? • Blushing • A result of vasodilation • Warm feeling • Cold extremeties due to loss of beta-adrenoceptor mediated vasodilation • Increased lumen size of blood vessels • More blood brought to vasodilated area •  Warm sensation • Common mode of action (except Hua Jiao) • Inhibit Ca2+ influx • Other Modes of actions • Increase NO • Increase cGMP • Activate TRPV1 • Alpha-adrenoceptor blockade 1Rang HP, Dale MM, Ritter JM, P.K. M. Pharmacology. 5th ed. Edinburgh ; New York: Churchill Livingstone, 2003

  13. Pharmacological Effects Possibly Linked to Interior Warming

  14. TRPV1 Agonism and its Relation to Interior Warming • Transient receptor potential ion channel of vanilloid type 1 • Highly expressed in a subset of primary sensory neurons of the trigeminal, vagal and dorsal root ganglia • Non-neuronal cells1 • Activation leads to many effects • Burning sensation • Vasodilation • via release of Calcitonin gene related peptide (CGRP) • Inhibit gastric leisions • Thermogenesis • Piperine, 6-gingerol, 10-gingerol, 6-shogaol Associated with vasoconstriction 1Geppetti P, Materazzi S, Nicoletti P. Eur J Pharmacol 2006;533(1-3):207-14.

  15. TRPV1 Agonism and its Relation to Interior Warming Effect Herb • Dual actions leading to the same warming effect or sensation? • TRPV1 causes both vasodilation and vasoconstriction under different conditions1 • Directly induce vascular smooth muscle contraction, linked to thermogenesis that is abolished by vasodilators • But release neuropeptides e.g. CGRP that causes vasodilation 6-shogaol 6-gingerol 6-shogaol 6-gingerol • TRPV1 agonists reported to result in hypothermia due to response to thermogenesis and activation of warm sensors1, • False sense of warmth • Not truly ‘therapeutic’ 1Eldershaw T, Colquhoun E, Bennett K et al. Life Sci 1994;55(5):389-97.

  16. Acknowledgement • Current Group Members: • Computer-Aided Drug Design: CY Ung, XH Ma, XH Liu, Pankaj Kumar, F Zhu, X Liu, J Jia • Protein Function, Interaction, Network: HL Zhang, CY Ung, XH Ma, F Zhu, WK Teo, Z Shi • Databases and Servers: J Jia • Medicinal Herb: CY Ung, Pankaj Kumar, Cao Jinyi(undergraduate students) • Microarray and biomarkers: J Jia, ZQ Tang • Former Members: • PhD: • ZW Cao (Prof SCBIT, Tongji U), ZL Ji (Assoc Prof Xiamen U), X Chen (Assoc Prof Zhejiang U), • CW Yap (Assist Prof NUS), LY Han (Postdoc NIH), CJ Zheng (Postdoc NIH), • HH Lin (Postdoc Harvard ), J Cui (Postdoc U Georgia), H Li (Postdoc Einstein College Med) • Research Fellow/Assistant: • ZR Li (Assoc Prof SiChuan U), Y Xue (Prof SiChuan U), W Liu (Assoc Prof DUT), • D Mi (Assoc Prof DUT), CZ Cai (Prof ChongQing U), DG Zhi (Postdoc, Berkeley), • MSc: • Y.J. Guo (Postdoc NIH), L.Z. Sun (RA, U Tenn.), J. F. Wang (MSU), L.X. Yao (Columbia), • S Ong (Washington U), H Zhou (local company), B Xie (local company) • BSc: • W.K. Yeo (IMCB, Novartis)

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