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  1. Article ; Online: Fragments: where are we now?

    Osborne, James / Panova, Stanislava / Rapti, Magdalini / Urushima, Tatsuya / Jhoti, Harren

    Biochemical Society transactions

    2020  Volume 48, Issue 1, Page(s) 271–280

    Abstract: Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical ... ...

    Abstract Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.
    MeSH term(s) Crystallography, X-Ray ; Drug Approval ; Drug Design ; Drug Discovery/methods ; Drug Discovery/trends ; Drug Evaluation, Preclinical/methods ; High-Throughput Screening Assays/trends ; Humans ; Magnetic Resonance Spectroscopy ; Protein Binding ; Small Molecule Libraries/chemistry
    Chemical Substances Small Molecule Libraries
    Language English
    Publishing date 2020-01-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20190694
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: A new school for screening.

    Jhoti, Harren

    Nature biotechnology

    2005  Volume 23, Issue 2, Page(s) 184–186

    MeSH term(s) Binding Sites ; Drug Delivery Systems/methods ; Drug Design ; Peptide Fragments/analysis ; Peptide Fragments/chemistry ; Peptide Library ; Phosphodiesterase Inhibitors/analysis ; Phosphodiesterase Inhibitors/chemistry ; Phosphoric Diester Hydrolases/analysis ; Phosphoric Diester Hydrolases/chemistry ; Protein Binding ; Protein Interaction Mapping/methods
    Chemical Substances Peptide Fragments ; Peptide Library ; Phosphodiesterase Inhibitors ; Phosphoric Diester Hydrolases (EC 3.1.4.-)
    Language English
    Publishing date 2005-02
    Publishing country United States
    Document type Comment ; News
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/nbt0205-184
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 137: Show issues
    Zs.MG 43: Show issues

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  3. Article ; Online: Structural genomics: lessons to be learnt.

    Jhoti, Harren

    Drug discovery today

    2001  Volume 6, Issue 24, Page(s) 1261–1262

    Language English
    Publishing date 2001-12-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/s1359-6446(01)02114-6
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  4. Article ; Online: High-throughput screening and structure-based approaches to hit discovery: is there a clear winner?

    Jhoti, Harren / Rees, Stephen / Solari, Roberto

    Expert opinion on drug discovery

    2013  Volume 8, Issue 12, Page(s) 1449–1453

    Abstract: Introduction: There are currently many lead discovery platforms available for drug discovery. Yet, it is often debated whether any of the available platforms are superior or standout to the other vast number of available technologies.: Areas covered: ...

    Abstract Introduction: There are currently many lead discovery platforms available for drug discovery. Yet, it is often debated whether any of the available platforms are superior or standout to the other vast number of available technologies.
    Areas covered: The authors comment, in this editorial, on the use and current state of the art of diversity-based high-throughput screening and how this has evolved and been improved from its earliest manifestations. They also describe structure- and computational-based drug discovery strategies and reflect on the differences between these two approaches.
    Expert opinion: Looking to the future, success in drug discovery is likely to depend on the intelligent deployment of multiple hit identification techniques, appropriate to the drug target, to identify and optimise novel drug leads. The authors' opinion is that there is no clear winner, but that each platform has its own particular strengths and different targets may be more amenable to one platform over another. The authors suggest that the most appropriate platform should be used on a case-by-case basis.
    MeSH term(s) Drug Discovery/methods ; High-Throughput Screening Assays ; Structure-Activity Relationship
    Language English
    Publishing date 2013-12
    Publishing country England
    Document type Editorial
    ZDB-ID 2259618-5
    ISSN 1746-045X ; 1746-0441
    ISSN (online) 1746-045X
    ISSN 1746-0441
    DOI 10.1517/17460441.2013.857654
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Fragment-based drug discovery using cryo-EM.

    Saur, Michael / Hartshorn, Michael J / Dong, Jing / Reeks, Judith / Bunkoczi, Gabor / Jhoti, Harren / Williams, Pamela A

    Drug discovery today

    2019  Volume 25, Issue 3, Page(s) 485–490

    Abstract: Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based ... ...

    Abstract Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).
    MeSH term(s) Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cryoelectron Microscopy/methods ; Drug Discovery/methods ; High-Throughput Screening Assays ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Reproducibility of Results ; Thyroid Hormones/chemistry ; Thyroid Hormones/metabolism ; beta-Galactosidase/chemistry ; beta-Galactosidase/metabolism ; Thyroid Hormone-Binding Proteins
    Chemical Substances Carrier Proteins ; Membrane Proteins ; Thyroid Hormones ; beta-Galactosidase (EC 3.2.1.23)
    Language English
    Publishing date 2019-12-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2019.12.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design.

    O'Reilly, Marc / Cleasby, Anne / Davies, Thomas G / Hall, Richard J / Ludlow, R Frederick / Murray, Christopher W / Tisi, Dominic / Jhoti, Harren

    Drug discovery today

    2019  Volume 24, Issue 5, Page(s) 1081–1086

    Abstract: We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5-7) to identify ligand-binding hot and warm spots on ... ...

    Abstract We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5-7) to identify ligand-binding hot and warm spots on proteins. We propose that MiniFrag screening represents a highly effective method for guiding optimisation of fragment-derived lead compounds or chemical tools and that the high screening hit rates reflect enhanced sampling of chemical space.
    MeSH term(s) Crystallography ; Drug Design ; Ligands ; Molecular Weight ; Small Molecule Libraries
    Chemical Substances Ligands ; Small Molecule Libraries
    Language English
    Publishing date 2019-03-14
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2019.03.009
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  7. Book: Structure-based drug discovery

    Jhoti, Harren / Leach, Andrew R

    2007  

    Author's details edited by Harren Jhoti, Andrew R. Leach
    MeSH term(s) Drug Design ; Structure-Activity Relationship ; Technology, Pharmaceutical/methods ; Computational Biology ; Amino Acid Sequence
    Language English
    Size xii, 249 p. :, ill. ;, 25 cm.
    Publisher Springer
    Publishing place Dordrecht
    Document type Book
    ISBN 9781402044069 ; 1402044062 ; 9781402044076 ; 1402044070
    Database Catalogue of the US National Library of Medicine (NLM)

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  8. Book ; Online: Structure-based drug discovery

    Jhoti, Harren / Leach, Andrew R

    (RSC biomolecular sciences ; [3])

    2007  

    Abstract: Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in ... ...

    Author's details ed. by Harren Jhoti; Andrew R. Leach
    Series title RSC biomolecular sciences ; [3]
    Abstract Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in this book. The book describes the latest developments in technologies that can be used to obtain the 3-D structures including the high profile structural genomics approaches being utilised worldwide. The use of 3-D protein structures in new, Fragment-based, approaches to drug discovery are described in some detail. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions. In addition, developments in computational chemistry methodology are covered together with an assessment of practical applications.

    This book describes some of the most exciting developments for the discovery of new drugs, such as Fragment-based methods. It contains the latest developments in technologies that can be used to obtain the 3-D structures. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions.
    MeSH term(s) Amino Acid Sequence ; Computational Biology ; Drug Design ; Structure-Activity Relationship ; Technology, Pharmaceutical/methods
    Keywords Biochemistry ; Chemistry ; Chemistry, Physical organic ; Pharmacy ; Medizin / Gesundheit Biochemie / Labormedizin
    Language English
    Size Online-Ressource, Ill., graph. Darst.
    Publisher Springer
    Publishing place Dordrecht
    Document type Book ; Online
    Note Includes bibliographical references and index
    ISBN 9781402044069 ; 9781402044076 ; 1402044062 ; 1402044070
    DOI 10.1007/1-4020-4407-0
    Database Former special subject collection: coastal and deep sea fishing

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  9. Book ; Online: Structure-based drug discovery

    Jhoti, Harren / Leach, Andrew R

    (RSC biomolecular sciences ; [3])

    2007  

    Abstract: Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in ... ...

    Author's details ed. by Harren Jhoti; Andrew R. Leach
    Series title RSC biomolecular sciences ; [3]
    Abstract Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in this book. The book describes the latest developments in technologies that can be used to obtain the 3-D structures including the high profile structural genomics approaches being utilised worldwide. The use of 3-D protein structures in new, Fragment-based, approaches to drug discovery are described in some detail. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions. In addition, developments in computational chemistry methodology are covered together with an assessment of practical applications.

    This book describes some of the most exciting developments for the discovery of new drugs, such as Fragment-based methods. It contains the latest developments in technologies that can be used to obtain the 3-D structures. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions.
    MeSH term(s) Amino Acid Sequence ; Computational Biology ; Drug Design ; Structure-Activity Relationship ; Technology, Pharmaceutical/methods
    Keywords Biochemistry ; Chemistry ; Chemistry, Physical organic ; Pharmacy ; Medizin / Gesundheit Biochemie / Labormedizin
    Language English
    Size Online-Ressource, Ill., graph. Darst.
    Publisher Springer
    Publishing place Dordrecht
    Document type Book ; Online
    Note Includes bibliographical references and index
    ISBN 9781402044069 ; 9781402044076 ; 1402044062 ; 1402044070
    DOI 10.1007/1-4020-4407-0
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  10. Book ; Online: Structure-based drug discovery

    Jhoti, Harren / Leach, Andrew R

    (RSC biomolecular sciences ; [3])

    2007  

    Abstract: Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in ... ...

    Author's details ed. by Harren Jhoti; Andrew R. Leach
    Series title RSC biomolecular sciences ; [3]
    Abstract Structure-based drug discovery methods have been transformed in the last 5-10 years and are now having a major impact on the discovery of new drugs. Some of the most exciting developments in the field, such as Fragment-based methods, are described in this book. The book describes the latest developments in technologies that can be used to obtain the 3-D structures including the high profile structural genomics approaches being utilised worldwide. The use of 3-D protein structures in new, Fragment-based, approaches to drug discovery are described in some detail. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions. In addition, developments in computational chemistry methodology are covered together with an assessment of practical applications.

    This book describes some of the most exciting developments for the discovery of new drugs, such as Fragment-based methods. It contains the latest developments in technologies that can be used to obtain the 3-D structures. This book includes experimental approaches using X-ray crystallography and NMR for Fragment-based screening as well as other biophysical methods for studying protein/ligand interactions.
    MeSH term(s) Amino Acid Sequence ; Computational Biology ; Drug Design ; Structure-Activity Relationship ; Technology, Pharmaceutical/methods
    Keywords Biochemistry ; Chemistry ; Chemistry, Physical organic ; Pharmacy ; Medizin / Gesundheit # Biochemie / Labormedizin ; Medizin / Gesundheit # Sonstiges ; Technik / Wissen # Biologie ; Technik / Wissen # Chemie
    Language English
    Size Online-Ressource, Ill., graph. Darst.
    Publisher Springer
    Publishing place Dordrecht
    Document type Book ; Online
    Note Includes bibliographical references and index
    ISBN 9781402044069 ; 9781402044076 ; 1402044062 ; 1402044070
    DOI 10.1007/1-4020-4407-0
    Database Special collection on veterinary medicine and general parasitology

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