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+ MODEL Journal of Traditional Chinese Medical Sciences (2017) xx, 1e8 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.elsevier.com/locate/jtcms In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs Yu-xin Zhang a,c, Xing Wang b,c, Shi-feng Wang a, Qiao Zhang a, Sha Peng a, Xi Li a, Yan-Ling Zhang a,*, Yan-Jiang Qiao a,** a Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Wangjing Zhonghuan South Road, Beijing 100102, China b Beijing Key Lab of Traditional Chinese Medicine (TCM) Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, 10 Youanmen, Xitoutiao, Beijing 100069, China Received 27 February 2016; received in revised form 30 December 2016; accepted 30 December 2016 Available online - - - KEYWORDS Five flavors; Pungent flavor; TRPM8; Pharmacophore; Pharmacological action Abstract Objective: Explicating the property and action of traditional Chinese medicine (TCM) in the perspectives of modern science deepens the insight into the property of TCM, and provides the basis for new drug discovery and clinical therapy In this study, we investigated the relationship between transient receptor potential melastatin (TRPM8) and pungent flavor using three-dimensional pharmacophores based on virtual screening methods Methods: Firstly, an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation Then, several therapeutic targets, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), cholesteryl ester transfer protein (CETP), Niemann-Pick C1-Like (NPC1L1) and platelet-activating factor receptor (PAFR), were selected to screen traditional Chinese herbs, and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets Results: According to the screening results, TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8, which shares the common virtual screening hits with the therapeutic targets, was considered to be related to the action of pungent taste * Corresponding author Fax: þ86 21 84738620 ** Corresponding author Fax: þ86 21 84738620 E-mail addresses: collean_zhang@163.com (Y.-L Zhang), yjqiao@263.net (Y.-J Qiao) Peer review under responsibility of Beijing University of Chinese Medicine c These authors are equally contributed to this article http://dx.doi.org/10.1016/j.jtcms.2016.12.005 2095-7548/ª 2017 Beijing University of Chinese Medicine Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 + MODEL Y.-x Zhang et al Conclusion: The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action ª 2017 Beijing University of Chinese Medicine Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/) Introduction Traditional Chinese herbs are defined by their characteristics, or properties The property theory (yao xing li lun) is based on the physiologic, pathologic, and clinical effects an herb has on the human body and guides syndrome pattern differentiation and prescription formulation As a whole, the property theory is composed of several aspects that describe the characteristics of an herb: four qi (temperature), five tastes, channel entered, directional tendency, and toxicity When combined, these characteristics impact one another, and yet form a unified ideology Applying scientific methods to explicate the characteristics of Chinese herbs deepens the understanding of the property theory and provides a foundation for discovery and clinical application of new drugs An herbal property of recent scientific interest is the five tastes The five tastes are: pungent (xin), sweet (gan), bitter (ku), sour (suan), and salty (xian) Each taste has a unique effect, or action, on the body In this study, we explored the pungent taste to scientifically validate the TCM concept that herbs pungent in flavor promote blood circulation (xin xing xue) and treat the TCM syndrome pattern, blood stasis Disorders caused by blood stasis include pain, numbness of the limbs, masses or lumps, among other problems associated with blood pathology Many of these herbs are used to treat biomedical conditions such as angina, hyperlipidemia, dysmenorrhea and so on Transient receptor potential (TRP) channels are belonging to a family of nonselective cation channels that are expressed in a diverse and large number of tissues, and have a wide variety of biologic roles.1,2 Some TRP channels are polymodal cell sensors, as they mediate an assortment of sensations such as temperature, touch, and taste.3,4 For example, channels that are associated with temperature are known as thermos TRPs.5 One TRP channel is TRP melastatin (TRPM8) It is activated when it is under cold environment and by the specific small compound like menthol.6,7 For this reason, this TRP channel is also known as the cold and menthol receptor (CMR1) Menthol is a compound found in mint (Mentha haplocalyx Briq.), a common herb used in Chinese medicine that is considered pungent in taste In this study, we investigated natural agonists of TRPs as well as their Chinese herbal sources and related properties to elucidate whether or not the TRPM8 ion channel may be the potential target by which an herb exhibits its pungent property Our investigation was accomplished through in silico methods that included multi-database mining and threedimensional pharmacophore construction The threedimensional pharmacophore construction method and multi-database mining methods have been used to study the relationship between pungent flavor and the corresponding effects under the guidance of TCM property theory First, a database of “Flavor-Action-Pharmacology” have been established and the correlation value between pharmacology and action have been calculated to identify the related pharmacological action according to the traditional Chinese herbs which have been designated as typical cases expressing the action of promoting blood circulation Then, in accordance with the identified action, TRPM8, 3hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR), cholesteryl ester transfer protein (CETP), NiemannPick C1-Like (NPC1L1) and platelet-activating factor receptor (PAFR) have been selected as typical targets to screen traditional Chinese herbs and the common virtual screening hits with various hit scores provide data to reveal the correlation among these targets Finally, according to the key sources of phytochemical hits, the preliminary results show that the pharmacological effects related to TRPM8 family ion channel is similar to “pungent property promotes blood circulation” effects and TRPM8 ion target is considered as the potential target through which TCM show pungent property Materials and methods Database establishment To identify the association of pharmacologic action with the pungent taste of herbs, we established a database, which we named Taste-Action-Pharmacology We chose 16 herbs listed in the Chinese Pharmacopoeia 20108 known for promoting blood circulation, or in TCM terminology, invigorating the blood, and are all pungent in taste (Table 1) Based on the Pharmacology of Chinese Materia Medica8, the pharmacologic actions of the herbs were then tagged with “1” (Table 2) If there was no corresponding action, no tag was designated Correlation between pungent taste and pharmacologic action To evaluate the correlation value between pungent taste and pharmacologic action of each of the 16 herbs, five parameters (T, X, C, Y, and M) were introduced and calculated as follows: C MZY Â CX C T CÂT Z YÂX T represents the total number of traditional Chinese herbs; X represents the number of compounds in herbs that improve blood circulation; Y is the number of herbs Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 + MODEL In silico investigation of the association Table Pungent herbs that promote blood circulation used to establish Taste-Action-Pharmacology database English name Latin name Chinese name Chuanxiong root Corydalis rhizome Dalbergia heartwood Lycopos Ligusticum chuanxiong Hort Corydalis yanhusuo W.T.Wang Dalbergia odorifera T.C.Chen Lycopus lucidus var hirtus Regel Leonurus japonicus Houtt Carthamus tinctorius L Commiphora myrrha Boswellia sacra Flueck Paeonia lactiflora Pall Curcuma zedoaria (Christm.) Roscoe Sparganium stoloniferum (Buch.-Ham ex Graebn.) Buch.-Ham ex Juz Mylabris phalerata Pallas Curcuma longa L chuanxiong Leonurus Safflower Myrrh Frankincense Red peony root Curcuma rhizome Sparganium Mylabris Turmeric rhizome Anomalous artemisia Tangkuei Musk yan hu suo jiang xiang ze lan yi mu cao hong hua mo yao ru xiang chi shao e zhu san leng ban mao jiang huang Artemisia anomala S.Moore liu ji nu Angelica sinensis (Oliv.) Diels Moschus berezovskii Flerov dang gui she xiang possessing specific pharmacologic actions; C is the number of herbs sharing the specific pharmacologic action of improving blood circulation When M is equal to 1, the correlation between pungent taste and the specific pharmacologic action is insignificant A higher value of M indicates a more pronounced correlation (Fig 1) Next, pharmacologic actions with highest scores were searched in the Drug Bank database (www.drugbank.ca) to define the drug targets associated with specific Table Fig Schema of parameters evaluating correlation between pungent taste and pharmacologic action pharmacologic activities In the current study, HMG-CoAR, CETP, NPC1L1, and PAFR were identified as targets for further study HMG-CoAR is the rate-limiting enzyme for hepatic cholesterol biosynthesis9 and its antagonists, the statins are commonly prescribed for preventing cardiovascular disease CETP inhibitors, attenuate cholesteryl ester hetero-exchange within the circulation.10 The drug, ezetimibe, blocks the NPC1L1, reduces cholesterol absorption, and results in a blood cholesterol reduction of between 15% and 20%.11 PAFR is a G-protein coupled receptor binding with PAF, which is a potent phospholipid activator involved in atherosclerosis.12,13 Generation of common feature pharmacophore model Pharmacophore is a specific three-dimensional model containing common characters of compounds that binding the same site of the target protein.14 Pharmacophore generation of TRPM8 was used as a model for determining the association between tastes and targets In this study, the HipHop algorithm15 (common feature pharmacophore generation) was used to build the pharmacophore of TRPM8 Pharmacophore model having highest CAI value of TRPM8 was selected to screen compounds the Traditional Chinese Medicine Database (TCMD; Version 2009)16 for agonists for Pharmacologic action of pungent Chinese herbs Pharmacologic action Analgesic Sedative Vasodilator Anticancer Anti-inflammatory Platelet inhibitor Anticoagulant Antimicrobial Anti-atherosclerotic Lipid lowering Improve circulation Fibrinolytic Chuanxiong root Corydalis rhizome 1 1 1 Turmeric rhizome Safflower Curcuma rhizome Sparganium 1 1 1 Red peony root 1 1 1 1 Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 + MODEL Y.-x Zhang et al further exploration of the association between the pungent taste and TRPM8 during pharmacophore generation These pharmacophore features characterize the interaction between the ligand and receptor Compounds and biologic data The studies were implemented on a series of TRPM8 agonists reported in the literature.17,18 Given the distribution of structural diversity, 11 compounds were selected to generate the pharmacophore model and the structures of agonists and their 50% effected concentrations (EC50) are shown in Fig Considering the biological activity with the chemical structure, CHEMBL258405, CHEMBL2087057, CHEMBL2087059, CHEMBL2087052, CHEMBL2087055, and CHEMBL2087056 were selected as training set Other agonists were used as the test set to validate the model Pharmacophore generation and validation Pharmacophore generation was accomplished as described below Conformation analysis The 3D qualitative pharmacophore hypotheses were constructed by HipHop in Discovery Studio 4.0 (Biovia, San Diego, CA) Ligand conformations were created by the best mode (best quality conformer generation) According to the Feature Mapping’s initial analysis by the mapping feature, which well-mapped all of the training set ligands, a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and aromatic ring (R) were selected Fig Pharmacophore generation and verification HipHop algorithm was used to generate pharmacophore model, which is a superposition of diverse conformations shared among the compounds Parameter of the procedure used the defined default value Compounds not used for pharmacophore model generation were used as an external test set for validating the pharmacophore hypotheses A test database of 11 experimentally known TRPM8 agonists embedded in a database consisting of 314 drug-like compounds (taken from the MDL Drug Database Report, Version 2007.2 http://www.mdli.com) was constructed to evaluate all of the pharmacophore models Identified ligands were filtered by Lipinski’s Rule of Five19 and were similar in chemical structural characteristics Furthermore, four parameters (A%, Y%, N, and CAI) were used to evaluate the performance of the models (Fig 3).20 Using the above methods, the pharmacophore models of HMG-CoAR, CETP, NPC1L1, and PAFR were generated The training set of each target is listed in the Supplementary data Virtual screening Based on the enrichment factor (CAI value) of the pharmacophore models, the highest scoring models were used for virtual screening of TRPM8 agonists, and antagonists of Chemical structures with EC50 of TRPM8 agonists Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 + MODEL In silico investigation of the association Fig Schema of indicators evaluating the pharmacophore models A% represents the ability to identify active compounds from the test database and Y% represents the proportion of active compounds in the hit compounds CAI, a comprehensive evaluation index, is used to identify the best pharmacophore model D is the total number of compounds in the test database and A is the number of active compounds The model with the highest value of CAI is considered to be the best HMG-CoAR, CETP, NPC1L1, and PAFR in Chinese herbs The model with highest CAI value served as the query to perform 3D flexible searching in Discovery Studio 4.0 to search the TCMD, which contains 23,033 natural compounds from 6735 medicinal plants Moreover, all potential hit compounds in the database should satisfy the Lipinski’s Rule of Five requirements Results Pharmacologic actions associated with the pungent taste Based on the formula for M value, 30 kinds of pharmacologic actions were used to compute their association with the pungent taste Ten of the best M values are shown in Table Pharmacophore model generation Eleven compounds of TRPM8 were used as the training set for a HipHop trial The top 10 pharmacophore models with calculation results are detailed in Table Two R features, an H feature and an A feature were contained in pharmacophore models; an R feature, two H features and an A feature were contained in pharmacophore models; an R feature, two H features, and a D feature were contained in pharmacophore model (Table 4) Both the direct hit and partial hit values of these 10 models were “111111” and Table Pharmacologic actions associated with the pungent taste Pharmacologic action M Improve circulation Blood viscosity reducer Vasodilator Antimicrobial Analgesic Platelet inhibitor Reduce myocardial oxygen demand Cardio excitatory Sedative Anti-inflammatory 3.33 2.50 2.00 1.67 1.67 1.43 1.25 1.25 1.25 1.11 Table Pharmacophore model calculation results Model Features Rank Direct hit Partial hit Max fit 10 RRHA RRHA RRHA RHHA RHHA RHHA RRHA RRHA RHHA RHHD 51.920 51.920 51.920 50.917 50.917 50.022 49.937 49.937 49.380 49.010 111111 111111 111111 111111 111111 111111 111111 111111 111111 111111 000000 000000 000000 000000 000000 000000 000000 000000 000000 000000 4 4 4 4 4 “000000,” which confirmed that all 11 compounds in the training set were considered in the generation of the models The “4” value of max fit validates that all features in the models matched the compounds in the training set The rank scores represented the degree of matching between the pharmacophore feature and the compounds In general, the higher the rank, the more satisfactory the model match Pharmacophore model validation Based on the diagram of indicators (Fig 4A) evaluating the pharmacophore models, the parameter value for each pharmacophore model is listed in Table Model had the highest CAI value and was thus selected to screen the TCMD 2009 database The pharmacophore feature of model mapped with ligand CHEMBL258405 (Fig 4B) Fig Pharmacophore model_2: (A) features and (B) the matching map with ligand Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 + MODEL Y.-x Zhang et al Table model Parameter values for each pharmacophore Model Aa Db Htc Had A%e Nf CAIg 10 11 11 11 11 11 11 11 11 11 11 314 314 314 314 314 314 314 314 314 314 64 63 63 100 114 118 70 73 124 86 9 8 9 9 81.82 81.82 81.82 72.73 72.73 81.82 81.82 81.82 81.82 81.82 4.15 4.22 4.22 2.36 2.07 2.25 3.80 3.64 2.14 3.09 3.40 3.45 3.45 1.72 1.51 1.84 3.11 2.98 1.75 2.53 a A is the number of active compounds D is the number of compounds in the test database c Ht is the number of hits using pharmacophore search d Ha is the number of active hits using pharmacophore search e A% represents the ability to identify active compounds in the test database f N represents the ability to identify active compounds from nonactive compounds g CAI is the comprehensive appraisal index b In summary, the pharmacophore model of HMG-CoAR, CETP, NPC1L1, and PAFR was generated and results of each target are listed in the Supplementary data Virtual screening of compounds To identify potential agonists of TRPM8, the pharmacophore model generated by HipHop was used to search compounds in TCMD 2009 Virtual screening yielded a hit list of 265 compounds with our desired pharmacologic activities Of the 265 compounds, 114 were from Chinese herbs listed in the Chinese Pharmacopoeia 2010.8 Of the 114 compounds, 71 (62.3%) were associated with the pungent taste (partial list in Table 6), indicating that the target TRPM8 bears some relation to the pungent taste Table Correlation analysis of pungent taste and pharmacologic action Based on the virtual screening results, hits not only interacted with TRPM8, but also with the ligands of HMGCoAR, CETP, NPC1L1, and PAFR, whose pharmacologic actions were among the 10 best M values (Table 3) The results (Table 7) provided the data to interpret the TCM concept that the pungent taste is associated with the pharmacologic action of promoting blood circulation Discussion According to the simulation results, menthol, eriodictyol and other “hit” compounds are derived from medicinal herbs with pungent flavor and cold property, such as M haplocalyx Moreover, the number of “Hit” compounds whose Hit Score higher than 3.0 is 94 and 62.8% compounds are from pungent TCM sources It indicated that the pharmacophore model of TRPM8 can gather the same structural characteristics of pungent TCM The model is capable to identify the compounds extracted from pungent TCM To evaluate the correlation value between “pungent taste” and pharmacological action, M parameter was calculated to determine its correlation A higher value of M indicates a more pronounced correlation between them As shown in Table 2, the pharmacological action of improving circulation, decreasing blood viscosity and expansion of blood vessels is closely related to its effect of “xin xing xue” The methods used in this study give us a profound inspiration for exploring the scientific connotation of five flavor theory, and it can be extended to solve similar problems in property study of Chinese medicines In this paper, TRPM8 target was studied through pharmacophore model and virtual screening to explore its relationship with pungent property However, in addition to the TRPV1 ion channel, the TRPs family includes a variety of other ion channels, such as TRPV, TRPA and so on One Partial virtual screening hits of TRPM8 agonists TCMD ID Hit score Hit compounds TCMD herb Taste 12514 12518 12513 12516 12517 12519 1621 12515 10829 19587 14634 7278 13774 22622 11236 8959 11699 3.30 3.26 3.10 3.10 3.10 3.09 2.93 2.93 2.84 2.68 2.45 2.10 2.07 2.03 1.90 1.77 1.35 Lappaol B Lappaol F Lappaol A Lappaol D Lappaol E Lappaol H L-arctigenin Lappaol C 40 -Hydroxy-wogonin Baicalin Methyl oleanolate Eriodictyol Menthol Prunellin b Isoarctigenin Gossypetin Isoscoparin Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Arctium lappa L (burdock seed) Scutellaria barbata D.Don (bearded scutellaria) Scutellaria barbata D.Don (bearded scutellaria) Prunella vulgaris L (prunella) Mentha haplocalyx Briq (mint) Mentha haplocalyx Briq (mint) Prunella vulgaris L (prunella) Arctium lappa L (burdock seed) Rhododendron dauricum L (rhododendron leaf) Lemna minor L (lesser duckweed) Pungent Pungent Pungent Pungent Pungent Pungent Pungent Pungent Pungent/Bitter Pungent/Bitter Pungent/Bitter Pungent Pungent Pungent/Bitter Pungent/Bitter Pungent/Bitter Pungent Abbreviation: TCM ID: ID number of Traditional Chinese Medicine Database Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 Partial list of compounds and their pharmacologic actions returned through virtual screening TCMD ID Compound TRPM8 HMG -CoAR CETP NPC1L1 PAFR Pharmacologic actions Herbal Source Taste 10870 17036 Scopolamine Peucenidin 3.49 3.20 2.18 2.98 3.23 Unknown 3.57 3.30 4.12 1.06 Vasodilator Vasodilator Datura metel L (devil’s trumpet flower) Peucedanum praeruptorum Dunn (peucedanum root) 7719 3.11 2.45 0.36 1.38 3.41 3.08 2.93 1.82 2.32 2.98 3.41 3.11 3.14 3.78 4.12 Blood viscosity reducer Unknown Anti-inflammatory Zanthoxylum species 19507 13474 Dimethoxy ashanti Nepitrin E Manasatin A Pungent Pungent/ Bitter Pungent 19402 Saucerneol 2.93 2.91 3.53 3.02 4.12 Improve circulation Saururus chinensis (Lour.) Baill 17550 4601 Plaunol C Dahuribirin E 2.88 2.78 3.04 1.12 1.96 2.82 y 2.82 3.16 2.59 Anti-inflammatory y 4602 Dahuribirin F 2.73 1.74 2.53 2.33 3.35 y 19587 Scutellarin 2.68 y 2.51 y 1.77 Platelet inhibitor Croton tiglium L (croton seed) Angelica dahurica (Hoffm.) Benth & Hook.f ex Franch & Sav (angelica root) Angelica dahurica (Hoffm.) Benth & Hook.f ex Franch & Sav (angelica root) Scutellaria barbata D.Don (bearded scutellaria) 1186 22882 4384 14554 4385 Anethole Kavalactones Curculigosaponin G Methyl linoleate Curculigoside 2.65 2.62 2.62 2.59 2.53 0.02 2.62 3.08 2.54 2.92 3.36 y 2.39 3.27 y y 1.90 y 3.28 y 0.71 3.43 y 3.79 y 17892 4386 Procyanidins C Curculigoside B 2.47 2.43 1.23 2.89 2.45 1.64 1.63 0.94 2.41 y 15438 11438 19497 4600 Neonootkatol Isogingerenone B Schizandrin C Dahuribirin D 2.34 2.33 2.32 2.29 2.15 1.70 1.98 3.05 y 0.78 2.98 3.01 1.01 0.25 y 2.24 3.43 0.49 1.35 2.66 Anti-inflammatory Sedative Anti-inflammatory y Reduce myocardial O2 demand y Reduce myocardial O2 demand y y y y 18636 16534 Resibufagin Mudanpioside A 2.27 2.20 2.79 y 2.76 2.75 2.20 1.88 2.78 2.58 17551 7278 12184 Plaunol D Eriodictyol Kavain 2.20 2.10 2.03 2.44 2.53 3.61 2.57 2.43 1.20 0.30 2.70 1.26 2.45 1.98 2.59 Pungent Pungent/ Sweet Pungent/ Sweet Pungent Pungent Pungent Carthamus tinctorius L (safflower) Curculigo orchioides Gaertn (curculigo) Pungent Pungent Alpinia oxyphylla Miq (alpinia fruit) Zingiber officinale Roscoe (dried ginger rhizome) Carthamus tinctorius L (safflower) Angelica dahurica Hoffm.) Benth & Hook.f ex Franch & Sav (angelica root) Bufo bufo gargarizans Cantor (toad venom) Paeonia lactiflora Pall (red peony root) Pungent Pungent Pungent Pungent Croton tiglium L (croton seed) Mentha haplocalyx Briq (mint) Piper nigrum L (pepper) MODEL Illicium verum Hook.f (star anise) Piper nigrum L (pepper) Curculigo orchioides Gaertn (curculigo) Ligusticum chuanxiong Hort (chuanxiong root) Curculigo orchioides Gaertn (curculigo) Pungent/ Bitter Pungent Pungent Pungent Pungent Pungent + y Reduce myocardial O2 demand Analgesia Antimicrobial Antibiosis Antimicrobial Schizonepeta tenuifolia Briq (Japanese catnip) Saururus chinensis (Lour.) Baill (lizard’s tail) In silico investigation of the association Pungent Pungent/ Bitter Pungent Pungent Pungent Abbreviations: CETP: cholesteryl ester transfer protein; HMG-CoAR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; NPC1L: 1Niemann-Pick C1-Like 1; PAFR: platelet-activating factor receptor; TCMD: Traditional Chinese Medicine Database; TRPM8: transient receptor potential melastatin Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 Table + MODEL Y.-x Zhang et al limitation to our study is that our pharmacophore model and virtual screening only used TRPM8 to explore its association with the pungent taste of Chinese herbs Therefore, only studying TRPM8 does not present a complete understanding of the association between the transient receptor potential channels and the pungent flavor of Chinese herbs Therefore, further study in this area is needed Appendix A Supplementary data Conclusions Venkatachalam K, Montell C TRP channels Annu Rev Biochem 2007;76:387e417 Gees M, Colsoul B, Nilius B The role of transient receptor potential cation channels in Ca2ỵ signaling Cold Spring Harb Perspect Biol 2010;2(10):231e234 Chaudhari N, Roper SD The cell biology of taste J Cell Biol 2010;190(3):285e296 Roper SD TRPs in taste and chemesthesis Handb Exp Pharmacol 2014;223:827e871 Laing RJ, Dhaka A ThermoTRPs and pain Neuroscientist 2015;22(2):171e187 Karashima Y, Damann N, Prenen J, et al Bimodal action of menthol on the transient receptor potential channel TRPA1 J Neurosci 2007;27(37):9874e9884 Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM More than cool: promiscuous relationships of menthol and other sensory compounds Mol Cell Neurosci 2006;32(4):335e343 National Pharmacopoeia Committee Pharmacopoeia of People Republic of China Part Beijing: Chemical Industry Press; 2010 Charlton-Menys V, Durrington PN Human cholesterol metabolism and therapeutic molecules Exp Physiol 2008;93(1): 27e42 10 Kwong M, Wasan KM Cholesteryl ester transfer protein facilitates the movement of water-insoluble drugs between lipoproteins: a novel biological function for a well-characterized lipid transfer protein Biochem Pharmacol 2002;64(12): 1669e1675 11 Temel RE, Tang W, Ma Y, et al Hepatic Niemann-Pick C1elike regulates biliary cholesterol concentration and is a target of ezetimibe J Clin Invest 2007;117(7):1968 12 Honda Z, Ishii S, Shimizu T Platelet-activating factor receptor J Biochem 2002;131(6):773e779 13 Iovino F, Brouwer MC, van de Beek D, Molema G, Bijlsma JJ Signalling or binding: the role of the platelet-activating factor receptor in invasive pneumococcal disease Cell Microbiol 2013;15(6):870e881 14 Koscova P, Provaznik I Pharmacophore modelling used in rational drug design Chem Listy 2016;110(8):575e580 15 Sutter J, Li J, Maynard AJ, Goupil A, Luu T, Nadassy K New features that improve the pharmacophore tools from Accelrys Curr Comput Aided Drug Des 2011;7(3):173e180 16 Traditional Chinese Medicine Database 2009 NeoSuite Beijing: NeoTrident; 2016 17 Bassoli A, Borgonovo G, Caimi S, et al Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens Bioorg Med Chem 2009;17(4):1636e1639 18 Ortar G, Morera L, Moriello AS, et al Modulation of thermotransient receptor potential (thermo-TRP) channels by thymol-based compounds Bioorg Med Chem 2012;22(10): 3535e3539 19 Nogara PA, Saraiva RA, Caeran BD, et al Virtual screening of acetylcholinesterase inhibitors using the Lipinski’s rule of five and ZINC databank Biomed Res Int 2015;2015:1e8 20 Wang X, Xiang Y, Ren Z, Zhang Y, Qiao Y Rational questing for inhibitors of endothelin converting enzyme-1 from Salvia miltiorrhiza by combining ligand-and structure-based virtual screening Can J Chem 2013;91(6):448e456 In this paper, a pharmacophore model based on virtual screening, data mining, combined with database construction was used to study the relationship between TRPM8 ion channel and pungent property The pharmacological action related to pungent flavor was identified based on the database of “Flavor-Action-Pharmacology” The correlation value between pharmacology and action was calculated to confirm pharmacological action correlated with pungent flavor Next, the pharmacology effect with highest scores has been searched in Drug Bank Database to define the targets associated with a specific pharmacological function And in the current study, HMGCoAR, CETP, NPC1L1 and PAFR were defined as the typical targets for further study Then, the pharmacophore hypothesis was developed and used to screen the in-house database for natural TRPM8 and therapeutic target agonists The results showed that the TRPM8 agonist pharmacophore model was able to specify/distinguish pungent herbs and identify the effective components from pungent herbs It also showed that the pharmacological effects related to the TRPM8 family ion channel are similar to “pungent property promotes blood circulation” effects Thus, the TRPM8 ion target is considered as the potential target through which TCM shows pungent property This paper provides a method for exploring the scientific relevance connotation of the five flavors theory of TCM With further study of TRPs ion channel family, the relationship and scientific interdependence connotation between TRPs family and the pungent property of TCM will be revealed and discovered ceaselessly Conflicts of interest The authors declare they have no conflicts of interest regarding the publication of this paper Author contributions YJ Qiao and YL Zhang conceived and designed the experiments YX Zhang and X Wang were involved in processing data and preparing the manuscript SF Wang participated in the discussion of views in the paper All authors have read and approved the final manuscript Acknowledgment This study was financially supported by a grant from National Science Foundation of China (Project No 81430094 and No 81603311) and Beijing Municipal Natural Science Foundation (No 7164239) Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jtcms.2016.12.005 References Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical Sciences (2017), http://dx.doi.org/10.1016/j.jtcms.2016.12.005 ... this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical... this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs, Journal of Traditional Chinese Medical... Traditional Chinese Medicine Database Please cite this article in press as: Zhang Yu-xin, et al., In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese

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