182:. Compounds contained in traditional medicines are usually more soluble than synthetic compounds, have âprivileged structuresâ (chemical structures that are more frequently found to bind in different living organisms), and have more comprehensively known safety and tolerance factors. Therefore, this makes them especially attractive as a resource for lead structures in when developing new molecular entities. Databases containing chemical structures of compounds used in alternative medicine along with their phenotypic effects, in silico analysis may be of use to assist in determining MOA for example, by predicting ligand targets that were relevant to known phenotypes for traditional medicines. In a case study for TCM, the therapeutic class of âtoning and replenishing medicineâ was evaluated. Therapeutic actions (or phenotypes) for that class include anti-inflammatory, antioxidant, neuroprotective, hypoglycemic activity, immunomodulatory, antimetastatic, and hypotensive.
139:
phenotypes by searching for molecules that interact specifically with a given protein. Both of these approaches require a suitable collection of compounds and an appropriate model system for screening the compounds and looking for the parallel identification of biological targets and biologically active compounds. The biologically active compounds that are discovered through forward or reverse chemogenomics approaches are known as modulators because they bind to and modulate specific molecular targets, thus they could be used as âtargeted therapeuticsâ.
17:
148:
tools to look for the protein responsible for the phenotype. For example, a loss-of-function phenotype could be an arrest of tumor growth. Once compounds that lead to a target phenotype have been identified, identifying the gene and protein targets should be the next step. The main challenge of forward chemogenomics strategy lies in designing phenotypic assays that lead immediately from screening to target identification.
1254:
157:
identify or confirm the role of the enzyme in the biological response. Reverse chemogenomics used to be virtually identical to the target-based approaches that have been applied in drug discovery and molecular pharmacology over the past decade. This strategy is now enhanced by parallel screening and by the ability to perform lead optimization on many targets that belong to one target family.
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Chemogenomics profiling can be used to identify totally new therapeutic targets, for example new antibacterial agents. The study capitalized on the availability of an existing ligand library for an enzyme called murD that is used in the peptidoglycan synthesis pathway. Relying on the chemogenomics
138:
Currently, there are two experimental chemogenomic approaches: forward (classical) chemogenomics and reverse chemogenomics. Forward chemogenomics attempt to identify drug targets by searching for molecules which give a certain phenotype on cells or animals, while reverse chemogenomics aim to validate
156:
In reverse chemogenomics, small compounds that perturb the function of an enzyme in the context of an in vitro enzymatic test will be identified. Once the modulators have been identified, the phenotype induced by the molecule is analyzed in a test on cells or on whole organisms. This method will
147:
In forward chemogenomics, which is also known as classical chemogenomics, a particular phenotype is studied and small compound interacting with this function are identified. The molecular basis of this desired phenotype is unknown. Once the modulators have been identified, they will be used as
240:
biosynthesis genes, they identified ylr143w as the strain with the highest cofitness to the all other strains lacking known diphthamide biosynthesis genes. Subsequent experimental assays confirmed that YLR143W was required for diphthamide synthesis and was the missing diphthamide synthetase.
110:
A common method to construct a targeted chemical library is to include known ligands of at least one and preferably several members of the target family. Since a portion of ligands that were designed and synthesized to bind to one family member will also bind to additional family members, the
239:
cofitness data. Cofitness data is data representing the similarity of growth fitness under various conditions between any two different deletion strains. Under the assumption that strains lacking the diphthamide synthetase gene should have high cofitness with strain lacking other diphthamide
190:(an insulin signaling regulator) were identified as targets which link to the hypoglycemic phenotype suggested. The case study for Ayurveda involved anti-cancer formulations. In this case, the target prediction program enriched for targets directly connected to cancer progression such as
201:
Beyond TCM and
Ayurveda, chemogenomics can be applied early in drug discovery to determine a compound's mechanism of action and take advantage of genomic biomarkers of toxicity and efficacy for application to Phase I and II clinical trials.
1177:
107:. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.
131:, chemogenomics techniques are able to modify the function of a protein rather than the gene. Also, chemogenomics is able to observe the interaction as well as reversibility in real-time. For example, the modification of a
235:(eEF-2). The first two steps of the biosynthesis pathway leading to dipthine have been known, but the enzyme responsible for the amidation of dipthine to diphthamide remained a mystery. The researchers capitalized on
546:
Bhattacharjee B, Simon RM, Gangadharaiah C, Karunakar P (Jun 2013). "Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in
Leptospira interrogans by virtual screening approaches".
476:
Mohd Fauzi F, Koutsoukas A, Lowe R, Joshi K, Fan TP, Glen RC, Bender A (Mar 2013). "Chemogenomics approaches to rationalizing the mode-of-action of traditional
Chinese and Ayurvedic medicines".
71:
and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets (
99:. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the
127:
functions. The interaction between a small compound and a protein induces a phenotype. Once the phenotype is characterized, we could associate a protein to a molecular event. Compared with
231:
was determined, chemogenomics was used to discover the enzyme responsible for the final step in its synthesis. Dipthamide is a posttranslationally modified histidine residue found on the
219:
inhibitors in experimental assays since peptidoglycan synthesis is exclusive to bacteria. Structural and molecular docking studies revealed candidate ligands for murC and murE ligases.
866:
745:
1172:
215:(murC, murE, murF, murA, and murG) to identify new targets for the known ligands. Ligands identified would be expected to be broad-spectrum
1214:
667:
648:
95:) have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as
899:
738:
183:
1283:
1246:
1192:
511:
Engelberg A (Sep 2004). "Iconix
Pharmaceuticals, Inc.--removing barriers to efficient drug discovery through chemogenomics".
582:
Cheung-Ong K, Song KT, Ma Z, Shabtai D, Lee AY, Gallo D, Heisler LE, Brown GW, Bierbach U, Giaever G, Nislow C (Nov 2012).
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175:
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can be observed only after addition of a specific compound and can be interrupted after its withdrawal from the medium.
376:
Caron PR, Mullican MD, Mashal RD, Wilson KP, Su MS, Murcko MA (Aug 2001). "Chemogenomic approaches to drug discovery".
111:
compounds contained in a targeted chemical library should collectively bind to a high percentage of the target family.
1136:
821:
100:
52:
584:"Comparative chemogenomics to examine the mechanism of action of dna-targeted platinum-acridine anticancer agents"
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264:
36:
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1027:
959:
236:
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76:
1208:
1124:
927:
892:
806:
305:
296:
Bredel M, Jacoby E (Apr 2004). "Chemogenomics: an emerging strategy for rapid target and drug discovery".
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similarity principle, the researchers mapped the murD ligand library to other members of the
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GLASS: A comprehensive database for experimentally-validated GPCR-ligand associations
637:
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335:
1061:
1022:
954:
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454:
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by using active compounds, which function as ligands, as probes to characterize
92:
48:
690:
1119:
1066:
1056:
1051:
781:
21:
677:
Weill N (2011). "Chemogenomic approaches for the exploration of GPCR space".
524:
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Matrix-assisted laser desorption ionization-time of flight mass spectrometer
1046:
713:
132:
698:
617:
568:
560:
532:
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462:
397:
327:
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Thirty years after the posttranslationally modified histidine derivative
908:
179:
128:
124:
64:
1007:
599:
489:
441:
Wuster A, Madan Babu M (May 2008). "Chemogenomics and biotechnology".
84:
60:
319:
718:
639:
Chemogenomics in drug discovery: a medicinal chemistry perspective
232:
187:
349:
Namchuk M (2002). "Finding the molecules to fuel chemogenomics".
766:
195:
68:
881:
727:
198:. These target-phenotype links can help identify novel MOAs.
877:
67:, etc.) with the ultimate goal of identification of novel
103:
for these targets can be used as a starting point for
1201:
1150:
1110:
998:
915:
635:Folkers G, Kubinyi H, MĂźller G, Mannhold R (2004).
636:
436:
434:
291:
289:
893:
739:
194:and synergistic targets like the efflux pump
8:
867:Quantitative structureâactivity relationship
478:Journal of Chemical Information and Modeling
24:robot retrieves assay plates from incubators
1173:Matrix-assisted laser desorption ionization
1241:
900:
886:
878:
746:
732:
724:
607:
549:Journal of Microbiology and Biotechnology
309:
170:Chemogenomics has been used to identify
15:
660:Chemogenomics: methods and applications
285:
223:Identifying genes in biological pathway
1215:European Molecular Biology Laboratory
679:Current Topics in Medicinal Chemistry
7:
119:Chemogenomics integrates target and
378:Current Opinion in Chemical Biology
14:
184:Sodium-glucose transport proteins
1253:
1252:
1240:
1193:Chromosome conformation capture
233:translation elongation factor 2
1:
1221:National Institutes of Health
455:10.1016/j.tibtech.2008.01.004
390:10.1016/S1367-5931(00)00229-5
363:10.1016/S1477-3627(02)02206-7
662:. Totowa, NJ: Humana Press.
206:Identifying new drug targets
176:traditional Chinese medicine
1137:Structure-based drug design
1315:
691:10.2174/156802611796391212
166:Determining mode of action
1236:
1227:Wellcome Sanger Institute
762:
413:"Chemogenomic techniques"
265:High-throughput screening
192:steroid-5-alpha-reductase
1183:Microfluidic-based tools
1028:Human Connectome Project
960:Human Microbiome Project
525:10.1517/14622416.5.6.741
237:Saccharomyces cerevisiae
1284:Computational chemistry
1168:Electrospray ionization
1040:Human Epigenome Project
822:Lipinski's rule of five
643:. Weinheim: Wiley-VCH.
443:Trends in Biotechnology
298:Nature Reviews Genetics
1209:DNA Data Bank of Japan
1125:Human proteome project
928:Computational genomics
561:10.4014/jmb.1206.06050
25:
1188:Isotope affinity tags
1142:Expression proteomics
827:Lipophilic efficiency
270:Personalized medicine
152:Reverse chemogenomics
143:Forward chemogenomics
19:
948:Human Genome Project
933:Comparative genomics
588:ACS Chemical Biology
275:Phenotypic screening
35:, is the systematic
1158:2-D electrophoresis
1132:Call-map proteomics
990:Structural genomics
977:Population genomics
938:Functional genomics
842:New chemical entity
832:Mechanism of action
756:medicinal chemistry
47:against individual
1112:Structural biology
923:Cognitive genomics
41:chemical libraries
26:
1268:
1267:
1163:Mass spectrometer
972:Personal genomics
875:
874:
817:Ligand efficiency
669:978-1-60761-273-5
658:Jacoby E (2009).
650:978-3-527-30987-0
600:10.1021/cb300320d
490:10.1021/ci3005513
419:on 23 August 2013
255:Chemical genetics
213:mur ligase family
57:nuclear receptors
33:chemical genomics
1306:
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1255:
1244:
1243:
1087:Pharmacogenomics
1082:Pharmacogenetics
902:
895:
888:
879:
852:Pharmacokinetics
847:Pharmacodynamics
812:Enzyme inhibitor
797:Drug development
748:
741:
734:
725:
719:Kubinyi's slides
702:
673:
654:
642:
622:
621:
611:
594:(11): 1892â901.
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513:Pharmacogenomics
508:
502:
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415:. Archived from
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250:Chemical biology
97:orphan receptors
51:families (e.g.,
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1299:Cheminformatics
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1102:Transcriptomics
1092:Systems biology
1077:Paleopolyploidy
1013:Cheminformatics
994:
911:
906:
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772:Bioavailability
758:
752:
710:
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685:(15): 1944â55.
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628:Further reading
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311:10.1.1.411.9671
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75:in the case of
45:small molecules
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357:(4): 125â129.
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555:(6): 779â84.
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384:(4): 464â70.
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217:Gram-negative
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29:Chemogenomics
23:
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1067:Microbiomics
1062:Metabolomics
1023:Connectomics
1017:
982:
955:Metagenomics
857:Pharmacology
776:
682:
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638:
591:
587:
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552:
548:
541:
519:(6): 741â4.
516:
512:
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481:
477:
471:
449:(5): 252â8.
446:
442:
421:. Retrieved
417:the original
411:Ambroise Y.
406:
381:
377:
371:
354:
350:
344:
301:
297:
226:
209:
200:
169:
161:Applications
155:
146:
137:
118:
109:
93:ion channels
39:of targeted
32:
28:
27:
1035:Epigenomics
967:Pangenomics
792:Drug design
229:diphthamide
49:drug target
1278:Categories
1120:Proteomics
1057:Lipidomics
1052:Immunomics
782:Drug class
754:Topics in
281:References
178:(TCM) and
174:(MOA) for
81:inhibitors
1047:Glycomics
306:CiteSeerX
133:phenotype
77:receptors
65:proteases
37:screening
1289:Genomics
1259:Category
985:genomics
909:Genomics
699:21470168
618:22928710
569:23676922
533:15335294
498:23351136
463:18346803
398:11470611
336:11952369
328:15131650
244:See also
180:Ayurveda
129:genetics
125:proteome
115:Strategy
89:blockers
1008:Biochip
609:3500413
423:28 July
351:Targets
85:enzymes
73:ligands
61:kinases
22:Staubli
916:Fields
697:
666:
647:
616:
606:
567:
531:
496:
461:
396:
334:
326:
308:
1223:(USA)
983:Socio
332:S2CID
188:PTP1B
87:, or
69:drugs
53:GPCRs
31:, or
1247:List
1229:(UK)
1217:(EU)
1211:(JP)
767:ADME
695:PMID
664:ISBN
645:ISBN
614:PMID
565:PMID
529:PMID
494:PMID
459:PMID
425:2013
394:PMID
324:PMID
196:P-gp
186:and
101:hits
687:doi
604:PMC
596:doi
557:doi
521:doi
486:doi
451:doi
386:doi
359:doi
316:doi
91:of
83:of
43:of
1280::
693:.
683:11
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