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      Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery

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          Abstract

          Knowledge and investigation of therapeutic targets (responsible for drug efficacy) and the targeted drugs facilitate target and drug discovery and validation. Therapeutic Target Database (TTD, http://bidd.nus.edu.sg/group/ttd/ttd.asp) has been developed to provide comprehensive information about efficacy targets and the corresponding approved, clinical trial and investigative drugs. Since its last update, major improvements and updates have been made to TTD. In addition to the significant increase of data content (from 1894 targets and 5028 drugs to 2025 targets and 17 816 drugs), we added target validation information (drug potency against target, effect against disease models and effect of target knockout, knockdown or genetic variations) for 932 targets, and 841 quantitative structure activity relationship models for active compounds of 228 chemical types against 121 targets. Moreover, we added the data from our previous drug studies including 3681 multi-target agents against 108 target pairs, 116 drug combinations with their synergistic, additive, antagonistic, potentiative or reductive mechanisms, 1427 natural product-derived approved, clinical trial and pre-clinical drugs and cross-links to the clinical trial information page in the ClinicalTrials.gov database for 770 clinical trial drugs. These updates are useful for facilitating target discovery and validation, drug lead discovery and optimization, and the development of multi-target drugs and drug combinations.

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          Most cited references39

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          Multi-target therapeutics: when the whole is greater than the sum of the parts.

          Drugs designed to act against individual molecular targets cannot usually combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory disorders. Combination drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in many important therapeutic areas. The combination drugs currently employed are primarily of rational design, but the increased efficacy they provide justifies in vitro discovery efforts for identifying novel multi-target mechanisms. In this review, we discuss the biological rationale for combination therapeutics, review some existing combination drugs and present a systematic approach to identify interactions between molecular pathways that could be leveraged for therapeutic benefit.
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            Mechanisms of drug combinations: interaction and network perspectives.

            Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.
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              Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.

              The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?
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                Author and article information

                Journal
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                January 2012
                January 2012
                30 September 2011
                30 September 2011
                : 40
                : D1 , Database issue
                : D1128-D1136
                Affiliations
                1Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543, 2NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, 3College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People's Republic of China, 4State Key Laboratory of Medicinal Chemistry & Biology, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, 5Computation and Systems Biology, Singapore-MIT Alliance, National University of Singapore 117543 and 6Computational Biology Program, National University of Singapore, Singapore 117543
                Author notes
                *To whom correspondence should be addressed. Tel: +65 6516 6877; Fax: +65 6774 6756; Email: csccyz@ 123456nus.edu.sg
                Article
                gkr797
                10.1093/nar/gkr797
                3245130
                21948793
                259b0a5b-a89a-4950-b29e-38511b973618
                © The Author(s) 2011. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 August 2011
                : 8 September 2011
                : 9 September 2011
                Page count
                Pages: 9
                Categories
                Articles

                Genetics
                Genetics

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