Therapeutic Targets Database

Therapeutic Target Database (TTD)
Content
DescriptionDrug target database
Contact
LaboratoryInnovative Drug Research and Bioinformatics Group (IDRB) Bioinformatics and Drug Design Group (BIDD)
Primary citationPMID 37713619
Release date1 Oct 2023
Access
Websitehttps://idrblab.org/ttd/
Miscellaneous
LicenseFree access
Version8.1.01

Therapeutic Target Database (TTD) is a pharmaceutical and medical repository[1] constructed by the Innovative Drug Research and Bioinformatics Group (IDRB) at Zhejiang University, China and the Bioinformatics and Drug Design Group at the National University of Singapore. It provides information about known and explored therapeutic protein and nucleic acid targets,[2] the targeted disease,[3] pathway information[4] and the corresponding drugs directed at each of these targets.[1] Detailed knowledge about target function, sequence, 3D structure, ligand binding properties, enzyme nomenclature and drug structure, therapeutic class, and clinical development status.[1] TTD is freely accessible without any login requirement at https://idrblab.org/ttd/.

Statistics

This database contains 3,730 therapeutic targets (532 successful, 1,442 clinical trial, 239 preclincial/patented and 1,517 research targets) and 39,862 drugs (2,895 approved, 11,796 clinical trial, 5,041 preclincial/patented and 20,130 experimental drugs). The targets and drugs in TTD cover 583 protein biochemical classes and 958 drug therapeutic classes, respectively.[1] The latest version of the International Classification of Diseases (ICD-11) codes released by WHO are incorporated in TTD to facilitate the clear definition of disease/disease class.[5]

Validation of Primary Therapeutic Target

Target validation normally requires the determination that the target is expressed in the disease-relevant cells/tissues,[6] it can be directly modulated by a drug or drug-like molecule with adequate potency in biochemical assay,[7] and that target modulation in cell and/or animal models ameliorates the relevant disease phenotype.[8] Therefore, TTD collects three types of target validation data:[9]

  • Experimentally determined potency of drugs against their primary target or targets.[6]
  • Evident potency or effects of drugs against disease models (cell-lines, ex-vivo, in-vivo models) linked to their primary target or targets.[8]
  • Observed effects of target knockout, knockdown, RNA interference, transgenetic, antibody or antisense treated in-vivo models.[7]

Categorization of Therapeutic Targets based on Clinical Status

The therapeutic targets in TTD are categorized into successful target, clinical trial target, preclinical target, patented target, and literature-reported target, which are defined by the highest status of their corresponding drugs.

  • Successful target: targeted by at least one approved drug;
  • Clinical trial target: not targeted by any approved drug, but targeted by at least one clinical trial drug;
  • Preclinical target: not targeted by any approved/clinical trial drug, but targeted by at least one preclinical drug;
  • Patented target: not targeted by any approved/clinical trial/preclinical drug, but targeted by at least one patented drug;
  • Literature-reported target: targeted by investigative drugs only.

Classification of Therapeutic Targets based on Molecular Types

The molecular types of therapeutic targets in TTD include protein, nucleic acid, and other molecule.

  • Protein: the most common type of target in drug development
  • Nucleic acid: include DNA, mRNA, miRNA, lncRNA targets
  • Other molecule: such as uric acid, iron, and reactive oxygen species

Different Types of Drugs Collected in TTD

The main drug types in TTD include small molecule, antibody, nucleic acid drug, cell therapy, gene therapy and vaccine.

  • Small molecule: the most common medications in the pharmaceutical market
  • Antibody: includes monoclonal antibodies and several alternatives such as antibody-drug conjugates, bispecific antibodies, IgG mixtures, and antibody fusion proteins
  • Nucleic acid drug: mainly include antisense oligonucleotides, small interfering RNAs, small activating RNA, microRNAs, mRNAs and so on
  • Cell therapy: inject, graft or implant viable cells into a patient in  to effectuate a medicinal effect
  • Gene therapy: manipulate gene expression or alter the biological properties of living cells to produce the therapeutic effect
  • Vaccine: provide active acquired immunity to a particular infectious or malignant disease

Main Advancement in Different Versions of TTD

2024 Update (Nucleic Acids Res. 2023, doi: 10.1093/nar/gkad751) [1]

■ Target druggability illustrated by molecular interactions or regulations;

■ Target druggability characterized by different human system features;

■ Target druggability reflected by diverse cell-based expression variations;

2022 Update (Nucleic Acids Res. 2022, 50: D1398-D1407) [10]

■ Structure-based activity landscape and drug-like property profile of targets;

■ Prodrugs together with their parent drug and target;

■ Co-targets modulated by approved/clinical trial drugs;

■ Poor binders and non-binders of targets;

2020 Update (Nucleic Acids Res. 2020, 48: D1031-D1041) [11]

■ Target regulators (microRNAs & transcription factors) and target-interacting proteins;

■ Patented agents and their targets (structures and experimental activity values if available);

2018 Update (Nucleic Acids Res. 2018, 46: D1121-D1127) [12]

■ Differential expression profiles and downloadable data of targets in patients and healthy individuals;

■ Target combination of multitarget drugs and combination therapies;

2016 Update (Nucleic Acids Res. 2016, 44: D1069-D1074) [13]

■ Cross-links of most TTD target and drug entries to the corresponding pathway entries;

■ Access of the multiple targets and drugs cross-linked to each of these pathway entries;

2014 Update (Nucleic Acids Res. 2014, 42: D1118-D1123) [14]

■ Biomarkers for disease conditions;

■ Drug scaffolds for drugs/leads;

2012 Update (Nucleic Acids Res. 2012, 40: D1128-D1136) [15]

■ Target validation information (drug-target-disease);

■ Quantitative structure activity relationship models (QSAR) for compounds;

2010 Update (Nucleic Acids Res. 2010, 38: D787-D791) [16]

■ Clinical trial drugs and their targets;

■ Similarity target and drug search.

References

  1. ^ a b c d e Zhou, Ying; Zhang, Yintao; Zhao, Donghai; Yu, Xinyuan; Shen, Xinyi; Zhou, Yuan; Wang, Shanshan; Qiu, Yunqing; Chen, Yuzong; Zhu, Feng (15 September 2023). "TTD: Therapeutic Target Database describing target druggability information". Nucleic Acids Research: gkad751. doi:10.1093/nar/gkad751. ISSN 1362-4962. PMC 10767903. PMID 37713619.
  2. ^ Hopkins AL, Groom CR (2002). "The druggable genome". Nature Reviews Drug Discovery. 1 (9): 727–30. doi:10.1038/nrd892. PMID 12209152. S2CID 13166282.
  3. ^ Overington JP, Al-Lazikani B, Hopkins AL (2006). "How many drug targets are there?". Nature Reviews Drug Discovery. 5 (12): 993–6. doi:10.1038/nrd2199. PMID 17139284. S2CID 11979420.
  4. ^ Zheng CJ, Han LY, Yap CW, Ji ZL, Cao ZW, Chen YZ (2006). "Therapeutic targets: progress of their exploration and investigation of their characteristics". Pharmacol. Rev. 58 (2): 259–79. doi:10.1124/pr.58.2.4. PMID 16714488. S2CID 3082221.
  5. ^ The Lancet, null (8 June 2019). "ICD-11". Lancet. 393 (10188): 2275. doi:10.1016/S0140-6736(19)31205-X. ISSN 1474-547X. PMID 31180012.
  6. ^ a b Lindsay, Mark A. (1 October 2003). "Target discovery". Nature Reviews. Drug Discovery. 2 (10): 831–838. doi:10.1038/nrd1202. ISSN 1474-1776. PMID 14526386. S2CID 40029453.
  7. ^ a b Vidalin, Olivier; Muslmani, Machadiya; Estienne, Clément; Echchakir, Hamid; Abina, Amine M. (1 October 2009). "In vivo target validation using gene invalidation, RNA interference and protein functional knockout models: it is the time to combine". Current Opinion in Pharmacology. 9 (5): 669–676. doi:10.1016/j.coph.2009.06.017. ISSN 1471-4973. PMID 19646923.
  8. ^ a b Overall, Christopher M.; Kleifeld, Oded (15 March 2006). "Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy". Nature Reviews. Cancer. 6 (3): 227–239. doi:10.1038/nrc1821. ISSN 1474-175X. PMID 16498445. S2CID 21114447.
  9. ^ Zhu, Feng; Shi, Zhe; Qin, Chu; Tao, Lin; Liu, Xin; Xu, Feng; Zhang, Li; Song, Yang; Liu, Xianghui; Zhang, Jingxian; Han, Bucong (1 January 2012). "Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery". Nucleic Acids Research. 40 (Database issue): D1128–1136. doi:10.1093/nar/gkr797. ISSN 1362-4962. PMC 3245130. PMID 21948793.
  10. ^ Zhou, Ying; Zhang, Yintao; Lian, Xichen; Li, Fengcheng; Wang, Chaoxin; Zhu, Feng; Qiu, Yunqing; Chen, Yuzong (7 January 2022). "Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents". Nucleic Acids Research. 50 (D1): D1398–D1407. doi:10.1093/nar/gkab953. ISSN 1362-4962. PMC 8728281. PMID 34718717.
  11. ^ Wang, Yunxia; Zhang, Song; Li, Fengcheng; Zhou, Ying; Zhang, Ying; Wang, Zhengwen; Zhang, Runyuan; Zhu, Jiang; Ren, Yuxiang; Tan, Ying; Qin, Chu (6 November 2019). "Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics". Nucleic Acids Research. 48 (D1): D1031–D1041. doi:10.1093/nar/gkz981. ISSN 1362-4962. PMC 7145558. PMID 31691823.
  12. ^ Li, Ying Hong; Yu, Chun Yan; Li, Xiao Xu; Zhang, Peng; Tang, Jing; Yang, Qingxia; Fu, Tingting; Zhang, Xiaoyu; Cui, Xuejiao; Tu, Gao; Zhang, Yang (4 January 2018). "Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics". Nucleic Acids Research. 46 (D1): D1121–D1127. doi:10.1093/nar/gkx1076. ISSN 1362-4962. PMC 5753365. PMID 29140520.
  13. ^ Yang, Hong; Qin, Chu; Li, Ying Hong; Tao, Lin; Zhou, Jin; Yu, Chun Yan; Xu, Feng; Chen, Zhe; Zhu, Feng; Chen, Yu Zong (4 January 2016). "Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information". Nucleic Acids Research. 44 (D1): D1069–1074. doi:10.1093/nar/gkv1230. ISSN 1362-4962. PMC 4702870. PMID 26578601.
  14. ^ Qin, Chu; Zhang, Cheng; Zhu, Feng; Xu, Feng; Chen, Shang Ying; Zhang, Peng; Li, Ying Hong; Yang, Sheng Yong; Wei, Yu Quan; Tao, Lin; Chen, Yu Zong (7 January 2014). "Therapeutic target database update 2014: a resource for targeted therapeutics". Nucleic Acids Research. 42 (Database issue): D1118–1123. doi:10.1093/nar/gkt1129. ISSN 1362-4962. PMC 3964951. PMID 24265219.
  15. ^ Zhu, Feng; Shi, Zhe; Qin, Chu; Tao, Lin; Liu, Xin; Xu, Feng; Zhang, Li; Song, Yang; Liu, Xianghui; Zhang, Jingxian; Han, Bucong; Zhang, Peng; Chen, Yuzong (8 January 2012). "Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery". Nucleic Acids Research. 40 (Database issue): D1128–1136. doi:10.1093/nar/gkr797. ISSN 1362-4962. PMC 3245130. PMID 21948793.
  16. ^ Zhu, Feng; Han, BuCong; Kumar, Pankaj; Liu, XiangHui; Ma, XiaoHua; Wei, Xiaona; Huang, Lu; Guo, YangFan; Han, LianYi; Zheng, ChanJuan; Chen, YuZong (7 January 2010). "Update of TTD: Therapeutic Target Database". Nucleic Acids Research. 38 (Database issue): D787–791. doi:10.1093/nar/gkp1014. ISSN 1362-4962. PMC 2808971. PMID 19933260.