Relenza (influenza neuraminidase inhibitor), and Celebrex
(COX-2 inhibitor) are just a few SBDD success stories that have
had a dramatic beneficial impact on human health. One of the
latest developments in SBDD is the screening of fragment-based
libraries.
Topics on the fragment-based approach to lead discovery form
the core of the book and are described in Chapters 3-6. Chapter
3 by Leach and Hann would have served well as the lead-in
chapter to the book because it presents a strong argument for
the advantages of fragment-based screening relative to other
methods of drug discovery. Unfortunately, the impact of this
perspective is diminished by a subsequent chapter (6) by Zhang
et al., who argue for an alternative scaffold-based approach.
The distinction between fragment-based and scaffold-based
seems to rely on a subtle difference in the definition of cutoff
in molecular weights. As a result, these two chapters appear
redundant. In fact, a common problem with the chapters on
fragment-based screening is the repetitive descriptions of library
design. Similarly, both the NMR and X-ray approaches to
screening fragment-based libraries have been exhaustively
reviewed in the literature.
The first two chapters present a progress report for the Joint
Center for Structural Genomics (JCSG). Given the rapid
development of structural genomics, the statistical details
presented by Abola et al. will be quickly outdated. Furthermore,
the high attrition numbers only illustrate a perceived disconnect
between the immediate value of structural genomics and SBDD.
Drug discovery programs do not operate by simply choosing a
protein that readily crystallizes in a high-throughput assay.
Instead, a better connection to SBDD should have been made
by emphasizing how structural genomics is expanding the
number of structures for therapeutic targets and how the
technology developed for structural genomics is being adapted
to SBDD.
An overview of the current challenges and limitations in
molecular docking are described by Verdonk et al. in Chapter
8. This is a solid overview with an informative and welldescribed
example that would have made a good introductory
chapter to discussions on the roles of molecular modeling in
fragment-based screening. Unfortunately this connection to
fragment-based screening is missing, illustrating the lack of
coherence in this book.
In Chapter 7, Chung and Lowe describe methodologies for
measuring affinity constants, an important component of drug
discovery. The authors were overly ambitious and tried to cover
every major analytical technique. The result is a general, cursory
list of methods that provides little insight, references, or
illustrative examples. Similarly, the final chapter by Fenu et al.
provides a comprehensive list of research focused on developing
an optimal scoring function, a fundamental problem in molecular
modeling and virtual screening. In an effort to be exhaustive,
very little detail is provided that illustrates how the various
approaches differ or how they are addressing a particular
Relenza (influenza neuraminidase inhibitor), and Celebrex
(COX-2 inhibitor) are just a few SBDD success stories that have
had a dramatic beneficial impact on human health. One of the
latest developments in SBDD is the screening of fragment-based
libraries.
Topics on the fragment-based approach to lead discovery form
the core of the book and are described in Chapters 3-6. Chapter
3 by Leach and Hann would have served well as the lead-in
chapter to the book because it presents a strong argument for
the advantages of fragment-based screening relative to other
methods of drug discovery. Unfortunately, the impact of this
perspective is diminished by a subsequent chapter (6) by Zhang
et al., who argue for an alternative scaffold-based approach.
The distinction between fragment-based and scaffold-based
seems to rely on a subtle difference in the definition of cutoff
in molecular weights. As a result, these two chapters appear
redundant. In fact, a common problem with the chapters on
fragment-based screening is the repetitive descriptions of library
design. Similarly, both the NMR and X-ray approaches to
screening fragment-based libraries have been exhaustively
reviewed in the literature.
The first two chapters present a progress report for the Joint
Center for Structural Genomics (JCSG). Given the rapid
development of structural genomics, the statistical details
presented by Abola et al. will be quickly outdated. Furthermore,
the high attrition numbers only illustrate a perceived disconnect
between the immediate value of structural genomics and SBDD.
Drug discovery programs do not operate by simply choosing a
protein that readily crystallizes in a high-throughput assay.
Instead, a better connection to SBDD should have been made
by emphasizing how structural genomics is expanding the
number of structures for therapeutic targets and how the
technology developed for structural genomics is being adapted
to SBDD.
An overview of the current challenges and limitations in
molecular docking are described by Verdonk et al. in Chapter
8. This is a solid overview with an informative and welldescribed
example that would have made a good introductory
chapter to discussions on the roles of molecular modeling in
fragment-based screening. Unfortunately this connection to
fragment-based screening is missing, illustrating the lack of
coherence in this book.
In Chapter 7, Chung and Lowe describe methodologies for
measuring affinity constants, an important component of drug
discovery. The authors were overly ambitious and tried to cover
every major analytical technique. The result is a general, cursory
list of methods that provides little insight, references, or
illustrative examples. Similarly, the final chapter by Fenu et al.
provides a comprehensive list of research focused on developing
an optimal scoring function, a fundamental problem in molecular
modeling and virtual screening. In an effort to be exhaustive,
very little detail is provided that illustrates how the various
approaches differ or how they are addressing a particular
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