| Over the last five decades, computational techniques that are routinely applied to structural elucidation in chemistry and biochemistry have become increasingly useful in diverse applications such as toxicological screening and rational drug design. Since the determination of myoglobin’s three-dimensional structure in 1958, the number of solved protein structures has climbed well into the tens of thousands. Now, pharmacophore development has become a routine step in the pharmaceutical industry for designing enzyme substrates that display enhanced specificity and selectivity, thus serving as better agonists or antagonists for native ligands. In addition, computational (in silico) methods for virtually screening chemicals for binding and toxicity analyses prior to in vivo laboratory studies using animal models are becoming more realistic, bringing us one step closer to reducing excessive animal testing prior to the marketing of a variety of chemical compounds.
With the obvious importance of this rapidly growing field to a diverse number of applications, it has become vital that this tool be available to students not only in the fields of chemistry and biochemistry but in areas of biology and bioinformatics as well. However, based on my personal experience, this subject is somewhat difficult to teach to students due to the depth and breadth of knowledge (or practice!) that is required to adequately appreciate both its potential benefits and the not-so-obvious limitations. Because of this, there have been few texts on molecular modeling that deliver adequate information in a concise fashion that are suitable to classroom teaching.
In Molecular Modeling: Basic Principles and Applications, Höltje, Sippl, Rognan, and Folkers attempt to correct this deficiency by providing a fairly detailed analysis of the steps involved in the molecular modeling process without delving too deeply into the complicated mathematical parameters that often seem to weigh down other texts. The result is a book that is relatively “student friendly”, providing instructors with sufficient detail and examples to explain many facets of the modeling process. Beginning with the concept of a model, the book progresses by explaining the various tools used for modeling small molecules. In doing so, they sufficiently describe the steps of generating molecular coordinates, optimizing geometry, and determining conformations and potentials. All of this leads up to and is reinforced by a case study that focuses on the development of a pharmacophore model for dopamine D3 receptor antagonists, a scenario that should impress upon the reader the amount of work that goes into the development of new pharmaceutical compounds.
Beginning with Chapter 4, the book begins the somewhat daunting task of explaining the steps involved in protein secondary and tertiary structure determination, briefly covering protein structure terminology and the primary methods of obtaining experimental data for structural calculations, namely X-ray crystallography and NMR spectroscopy. Focusing more on comparative protein modeling, this section does an adequate job of explaining how one uses online tools such as BLAST and FASTA to search collections of proteins with similar sequence homology in order to determine potential structural motifs for a given amino acid sequence.
Changing gears somewhat, Chapter 5 walks the reader through the process of in silico virtual screening, describing various docking programs that are routinely used to test large libraries of potential ligands for their ability to bind to the active sites of known enzyme receptors. A discussion of the types of information that are obtained during such processes (for example, scoring functions) as well as the limitations and potential pitfalls of such information are also briefly covered.
Progressing in complexity, Chapter 7 presents a thorough case study analyzing a protein-ligand complex. The example given focuses on the binding of a viral peptide with a class I major histocompatability protein, coalescing all of the techniques that are described in the previous chapters into one example that clearly illustrates to the reader just how involved such modeling studies can become. Homology modeling of the protein (against a known protein with 70% homology), ligand modeling and docking, molecular dynamics of the resulting protein-ligand complex, and the design and testing of new ligands are all described in sufficient detail to provide a summary of the entire book in one complete application.
In general, I feel that this book provides a sufficient level of detail describing the steps involved in molecular modeling for use in teaching an upper-level undergraduate or introductory graduate level course on biochemistry and rational drug design. Overall, I think it is one of the better texts on the subject that I have had an opportunity to read. The only areas of improvement that I would suggest would be an expansion on the discussion of how experimental data from X-ray crystallography and NMR spectroscopy are formatted for use in modeling calculations and perhaps the addition of supplemental examples that require input from the reader, possibly in the form of a CD-ROM that will give students the opportunity to try their own hand at modeling so that they may fully appreciate the labor that is involved and the results that are obtained.
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