Computer automated prediction of potential therapeutic and toxicity protein targets of bioactive compounds from Chinese medicinal plants.

Understanding the molecular mechanism and pharmacology of bioactive compounds from Chinese medicinal plants (CMP) is important in facilitating scientific evaluation of novel therapeutic approaches in traditional Chinese medicine. It is also of significance in new drug development based on the mechanism of Chinese medicine. A key step towards this task is the determination of the therapeutic and toxicity protein targets of CMP compounds. In this work, newly developed computer software INVDOCK is used for automated identification of potential therapeutic and toxicity targets of several bioactive compounds isolated from Chinese medicinal plants. This software searches a protein database to find proteins to which a CMP compound can bind or weakly bind. INVDOCK results on three CMP compounds (allicin, catechin and camptotecin) show that 60% of computer-identified potential therapeutic protein targets and 27% of computer-identified potential toxicity targets have been implicated or confirmed by experiments. This software may potentially be used as a relatively fast-speed and low-cost tool for facilitating the study of molecular mechanism and pharmacology of bioactive compounds from Chinese medicinal plants and natural products from other sources.

[1]  R. Favoni,et al.  Steroidal and nonsteroidal oestrogen antagonists in breast cancer: basic and clinical appraisal. , 1998, Trends in pharmacological sciences.

[2]  S. Gupta,et al.  Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells. , 2000, Toxicology and applied pharmacology.

[3]  W. Lei,et al.  Pharmacodynamics and Toxicodynamics of Drug Action: Signaling in Cell Survival and Cell Death , 1999, Pharmaceutical Research.

[4]  A. Starkov,et al.  Mitochondrial targets of drug toxicity. , 2000, Annual review of pharmacology and toxicology.

[5]  Y. Z. Chen,et al.  Prediction of potential toxicity and side effect protein targets of a small molecule by a ligand-protein inverse docking approach. , 2001, Journal of molecular graphics & modelling.

[6]  E. Gillam,et al.  Immunotoxic Side-Effects of Drug Therapy , 1990, Drug safety.

[7]  A. Kaye,et al.  Analysis of responses of garlic derivatives in the pulmonary vascular bed of the rat. , 2000, Journal of applied physiology.

[8]  Schmidt Tj,et al.  Autoregulation of corticosteroid receptors. How, when, where, and why? , 1994 .

[9]  T. Lennard,et al.  Therapeutic applications of medicinal plants in the treatment of breast cancer: a review of their pharmacology, efficacy and tolerability. , 2000, Adverse drug reactions and toxicological reviews.

[10]  Y.Z. Chen,et al.  Ligand–protein inverse docking and its potential use in the computer search of protein targets of a small molecule , 2001, Proteins.

[11]  N. Brattig,et al.  Immunoenhancing effect of flavonoid compounds on lymphocyte proliferation and immunoglobulin synthesis. , 1984, International journal of immunopharmacology.

[12]  Yan P. Yuan,et al.  Predicting function: from genes to genomes and back. , 1998, Journal of molecular biology.

[13]  K. T. Augusti,et al.  Studies on the effect of allicin (diallyl disulphide-oxide) on alloxan diabetes. I. Hypoglycaemic action and enhancement of serum insulin effect and glycogen synthesis. , 1973, Indian journal of biochemistry & biophysics.

[14]  Zhu Da-yuan,et al.  Recent studies on traditional Chinese medicinal plants , 1996 .

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

[16]  D. Gingras,et al.  Matrix metalloproteinase inhibition by green tea catechins. , 2000, Biochimica et biophysica acta.

[17]  Sense and non-sense in toxicity assessment of medicinal products , 1997 .

[18]  G. Hageman,et al.  Antibacterial effect of garlic and omeprazole on Helicobacter pylori. , 1999, The Journal of antimicrobial chemotherapy.

[19]  D. Shalinsky,et al.  Inhibition of GSH-dependent PGH2 isomerase in mammary adenocarcinoma cells by allicin. , 1989, Prostaglandins.

[20]  H. Dodds,et al.  The mechanism for the inhibition of acetylcholinesterases by irinotecan (CPT-11). , 1999, Molecular pharmacology.

[21]  D. Wang,et al.  Chromatography of medicinal plants and Chinese traditional medicines. , 1998, Biomedical chromatography : BMC.

[22]  J A McCammon,et al.  Accommodating protein flexibility in computational drug design. , 2000, Molecular pharmacology.

[23]  G. Polya,et al.  Inhibition of eukaryote signal-regulated protein kinases by plant-derived catechin-related compounds. , 1994, Phytochemistry.

[24]  M. Sutter,et al.  Recent cardiovascular drugs from Chinese medicinal plants. , 1993, Cardiovascular research.

[25]  Jen-kun Lin,et al.  Inhibition of cyclin‐dependent kinases 2 and 4 activities as well as induction of cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (−)‐epigallocatechin‐3‐gallate , 1999, Journal of cellular biochemistry.

[26]  S. Ankri,et al.  Antimicrobial properties of allicin from garlic. , 1999, Microbes and infection.

[27]  A. Sali.  100,000 protein structures for the biologist , 1998, Nature Structural Biology.

[28]  B. Shoichet,et al.  Flexible ligand docking using conformational ensembles , 1998, Protein science : a publication of the Protein Society.

[29]  S. Gupta,et al.  Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. , 2000, Archives of biochemistry and biophysics.

[30]  H. Tsuchiya.  Effects of Green Tea Catechins on Membrane Fluidity , 1999, Pharmacology.

[31]  M. Ali,,et al.  Effect of allicin from garlic powder on serum lipids and blood pressure in rats fed with a high cholesterol diet. , 2000, Prostaglandins, leukotrienes, and essential fatty acids.

[32]  H. Ahn,et al.  Green tea compounds inhibit tyrosine phosphorylation of PDGF β‐receptor and transformation of A172 human glioblastoma , 2000, FEBS letters.

[33]  F. Wang,et al.  Protein tyrosine phosphatase-dependent activation of beta-globin and delta-aminolevulinic acid synthase genes in the camptothecin-induced IW32 erythroleukemia cell differentiation. , 1997, Molecular pharmacology.

[34]  K. Chan,et al.  Progress in traditional Chinese medicine. , 1995, Trends in pharmacological sciences.

[35]  Z. Dong,et al.  Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved. , 1999, Cancer research.

[36]  Y. Pommier,et al.  Apoptotic response to camptothecin and 7‐hydroxystaurosporine (UCN‐01) in the 8 human breast cancer cell lines of the NCI anticancer drug screen: Multifactorial relationships with topoisomerase i, protein kinase C, Bcl‐2, p53, MDM‐2 and caspase pathways , 1999, International Journal of Cancer.

[37]  E. Solary,et al.  Increased gadd153 messenger RNA level is associated with apoptosis in human leukemic cells treated with etoposide. , 1997, Cancer research.

[38]  G. Baldini,et al.  The pro-apoptotic drug camptothecin stimulates phospholipase D activity and diacylglycerol production in the nucleus of HL-60 human promyelocytic leukemia cells. , 1999, Cancer research.

[39]  X. Chen,et al.  TTD: Therapeutic Target Database , 2002, Nucleic Acids Res..

[40]  D. E. Clark,et al.  Flexible docking using tabu search and an empirical estimate of binding affinity , 1998, Proteins.

[41]  Juei-Tang Cheng,et al.  Review: Drug Therapy in Chinese Traditional Medicine , 2000, Journal of clinical pharmacology.

[42]  Kailash Prasad,et al.  Antioxidant activity of allicin, an active principle in garlic , 1995, Molecular and Cellular Biochemistry.

[43]  K. Agarwal.  Therapeutic actions of garlic constituents , 1996, Medicinal research reviews.

[44]  R Yuan,et al.  Traditional Chinese medicine: an approach to scientific proof and clinical validation. , 2000, Pharmacology & therapeutics.

[45]  Jen-kun Lin,et al.  Suppression of extracellular signals and cell proliferation through EGF receptor binding by (−)‐epigallocatechin gallate in human A431 epidermoid carcinoma cells , 1997, Journal of cellular biochemistry.

[46]  B Rost,et al.  Bridging the protein sequence-structure gap by structure predictions. , 1996, Annual review of biophysics and biomolecular structure.

[47]  George W. A. Milne,et al.  Chem-X and CAMBRIDGE. Comparison of computer generated chemical structures with x-ray crystallographic data , 1993, J. Chem. Inf. Comput. Sci..

[48]  A. Komori,et al.  Anticarcinogenic activity of green tea polyphenols. , 1993, Japanese journal of clinical oncology.

[49]  K. Lee.  Novel antitumor agents from higher plants , 1999, Medicinal research reviews.

[50]  I. Kuntz,et al.  Flexible ligand docking: A multistep strategy approach , 1999, Proteins.

[51]  B. X. Carlson,et al.  A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor beta(2) subunit affects allosteric sensitivity to GABA and anesthetics. , 2000, Molecular pharmacology.

[52]  N. Sucher,et al.  Stroke therapy in traditional Chinese medicine (TCM): prospects for drug discovery and development. , 1999, Trends in pharmacological sciences.

[53]  E. Castanas,et al.  Potent inhibitory action of red wine polyphenols on human breast cancer cells , 2000, Journal of cellular biochemistry.

[54]  B. Hwang,et al.  (-)-Epiafzelechin: cyclooxygenase-1 inhibitor and anti-inflammatory agent from aerial parts of Celastrus orbiculatus. , 1999, Planta medica.

[55]  L. Bohlin,et al.  Flavan-3-ols Isolated from Some Medicinal Plants Inhibiting COX-1 and COX-2 Catalysed Prostaglandin Biosynthesis , 1998, Planta medica.