Why mechanism of herbs? Why computer approach? How it works? Performance Analysis and future plan Lecture 8: Drug Target Identification and Mechanistic Study of Herbs Y.Z Chen Dept. of Comptational Science National University of Singapore

Herbal Medicine and Society Widely used in Asian ( China, India, Japan, Korea, Singapore etc. ) and other nations ( 120 nations established relevant organizations and facilities, as reported by XinHua news agency in 24/2/2000 ). Increased popularity in western countries ( 12% of the population in USA used herbal medicine in 1997, as reported in Journal of American Medical Association ). Important sources for new drug discovery ( 1/3 of top selling drugs in the market derived from herbal ingredients, as reported in Drug Discovery Today ). Increased R&D investment in North America, Europe, Japan, China, Taiwan, and Hong Kong. Singapore established a TCM taskforce since 2000.

How Western Drugs Work? Drug Therapeutic Target (Disease related protein) => Beneficial effect Toxicity and side-effect inducing proteins => Adverse effects One drug, single therapeutic target Drug optimized with the best therapeutic effect

How Herbal Products Work? Synergy of Multiple Herbal Ingredients Aganist Multiple Targets  Mixture of multiple herbs:  Actions > Simple sum  Synergy:  Mutual enhancement  Mutual counteraction  Maintenance and balance  Multiple targets:  Therapeutics  Symptom treatment  Toxicity/side effect modulation  Drug delivery and clearance  Boost of immune system  Energy, PH, temperature balance/restoration  Harmonization Pharmacology & Therapeutics 2000, 86:

Why Mechanism of Herbal Products? Current and future work necessary to advance herbal medicines:  Standardization in herbal composition  Analytic chemistry  Scientific proof and optimization  Need info about the related targets  Discovery of novel cocktail approaches:  Need understanding of how herbal ingredients work in synergy.

Why Computer Approach? Existing experimental methods costly and time-consuming. Limited resources: Limited availability of herbs Difficulty in chemical synthesis and bioassay. Feasibility of computer approach: Information availability: herbal ingredients, disease and toxicity related proteins. Software technology: INVDOCK and machine learning. Computer capacity: Higher speed and lower cost

How It Works? Computer Match-Making Y.Z. Chen and D.G. Zhi Proteins 2001;43: 217 Herbal Formula Database  Herbal Ingredient Database  Therapeutic Target Database   Drug Adverse Reaction Target Database   Drug Absorption Distribution Metabolism Excretion Database   Computer Match-Making Software  Herbal Ingredient Therapeutic Target Toxicity Target ADME protein  Collective therapeutic and maintenance effects  Toxicity / side effects and modulation  Drug delivery and clearance Matched Pairs Mutual Enhancement ? Mutual Counteraction ? Maintenance or Balance ? Delivery or Clearance ?

Gingko as An Example: Ingredients in Its Leaf Extract Flovone glycosides (flavonoids) Quercetin, kaempferol, isorhamnetin, ginkgetin…. Terpene lactones (terpenoids) Ginkgolides: A,B,C, J and M… Bilobalides: A, B ….. Phenols Ginkgolic acid, hydroginkgolic acid, ginkgolinic acid, ginkgol, bilobol…. Organic acids Alcohol groups Quinic acid, linoleic acid, shikimic acid, asorbic acid, formic acid, propionic acid… hexenol, sequoyitol Vitamins and others Vc, carotenoids, iron…. More than 45 compounds found so far.

Gingko as an Example: Query Results from HICD

   Selection criterion

Gingko as an Example: Query Results from Database Search  

Structure of Important Active Ingredients in Gingko Leaf Extract *

Identified Therapeutic Targets of Quercetin Identified Theraputic Targets By computer Experimental FindingsTarget statusTherapeutic Implication Phospholipase A2Potent inhibitor to group II PLA2 ConfirmedInflammation, Neuro-related disease Protein Kinase CInhibits the phosphorylating activity ImplicatedHeart disease, Cancer, Stress related, Brain disease, Asthma Estrogen ReceptorBinds to type II estrogen binding site Confirmed Breast Cancer MAP KinaseInhibit p38 MAPK activity ImplicatedArthritis, Asthma Y. Z. Chen, etc. American Journal of Chinese Medicine, 30, (2002).American Journal of Chinese Medicine

Predicted and Observed Therapeutic Effects of GingKo Therapeutic Effects of Identified Therapeutic Targets Therapeutic Effects Observed Memory and learning enhancement Treatment of memory loss Anti-cancer Beneficial to Gastric, colorectal, pancreatic cancer Anti-arthritis Dose-dependant inhibition arthritis (only 1 report) Anti-Inflammation Treatment of bladder inflammation Treating heart disease Contribution to cardiovascular disease Treating asthma Remedy against asthma, coughs Neuro-protective function Slowing down the progression of Alzheimer’s disease Indigestion improvement No report Improvement of Vaso-dilation/contraction Stimulation of blood circulation

Comparison Between Prediction and Experiments Medicinal PlantPotential Therapeutic Targets Identified Experimentally Confirmed and Implicated So Far Percentage Gingko % Ginseng ( ginsenosides) 6 583% Serenoa Repens % Citrus Fruit (Flavonoids) %