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      Current NMR Techniques for Structure-Based Drug Discovery

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          Abstract

          A variety of nuclear magnetic resonance (NMR) applications have been developed for structure-based drug discovery (SBDD). NMR provides many advantages over other methods, such as the ability to directly observe chemical compounds and target biomolecules, and to be used for ligand-based and protein-based approaches. NMR can also provide important information about the interactions in a protein-ligand complex, such as structure, dynamics, and affinity, even when the interaction is too weak to be detected by ELISA or fluorescence resonance energy transfer (FRET)-based high-throughput screening (HTS) or to be crystalized. In this study, we reviewed current NMR techniques. We focused on recent progress in NMR measurement and sample preparation techniques that have expanded the potential of NMR-based SBDD, such as fluorine NMR ( 19F-NMR) screening, structure modeling of weak complexes, and site-specific isotope labeling of challenging targets.

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          Principles of early drug discovery.

          Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12-15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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            Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

            The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.
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              From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

              The B cell lymphoma 2 (BCL-2) family of proteins has a key role in regulating apoptosis and is often dysregulated in cancer. This has led to the development of several inhibitors of pro-survival BCL-2 family proteins such as BCL-2, BCL-XL and MCL1, including the BCL-2 inhibitor venetoclax, which has recently gained regulatory approval. Here, Ashkenazi and colleagues discuss the latest progress in developing small-molecule inhibitors of pro-survival BCL-2 family proteins.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                MDPI
                1420-3049
                12 January 2018
                January 2018
                : 23
                : 1
                Affiliations
                [1 ]Institute for Protein Research, Osaka University, Osaka 565-0871, Japan; sugiki@ 123456protein.osaka-u.ac.jp (T.S.); k-furuit@ 123456protein.osaka-u.ac.jp (K.F.); tfjwr@ 123456protein.osaka-u.ac.jp (T.F.)
                [2 ]Graduate School of Engineering, Yokohama National University, Yokohama 240-8501, Japan
                Author notes
                [* ]Correspondence: kojima-chojiro-xk@ 123456ynu.ac.jp ; Tel.: +81-45-339-4232
                Article
                molecules-23-00148
                10.3390/molecules23010148
                6017608
                29329228
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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