By Hallie Metzger and Lloyd Irland. Admirable traffic: Watching the great bird highway. By Katherine Hauswirth. 25 BOOK REVIEWS. Reviews of a. This is the beautiful way in which Nature gets her muck, while I chaffer with this man and that, who talks to me about sulphur and the cost of carting. Biography Caterina Bissantz earned her Pharm.D. (1998) from University of Freiburg, Germany, her M.Sc. (1999) from Purdue University, West Lafayette, IN, under the supervision of Dr. Don Bergstrom in the field of synthetic medicinal chemistry, and her Ph.D. (2002) from ETH Zurich, Switzerland, under the supervision of Prof. Gerd Folkers and Dr. Didier Rognan in the field of virtual screening and GPCR modeling. In 2002, she joined Roche, where she is a member of the Molecular Design Group. Her special areas of interest are structure-based and GPCR drug design. She has coauthored more than 40 papers and patents. Biography Bernd Kuhn received his M.S. In Chemistry (1994) from the University of Karlsruhe, Germany, and Ph.D. (1998) from the Swiss Federal Institute of Technology, Lausanne, Switzerland, under the supervision of Prof. Following postdoctoral studies as a DAAD fellow in macromolecular simulations with Prof. Peter Kollman at the University of California, San Francisco, he joined the start-up company Prospect Genomics in 2000. In 2001 he moved to F. Hoffmann-La Roche, Basel, Switzerland, where he is a member of the Molecular Design group with a focus on structure-based computational methods and their application to drug design projects. His scientific contributions include more than 90 papers and patents. Biography Martin Stahl received his Ph.D. In Theoretical Chemistry from the University of Marburg, Germany, under the supervision of Prof. He joined Roche in 1997 and initially worked on structure-based design projects at the Basel and Palo Alto sites. In 2001, he was appointed head of molecular design in Basel. Since 2005, he has been a section head in medicinal chemistry. A member of the global chemistry leadership team, he is responsible for the Roche-wide coordination of molecular design and cheminformatics work. He has helped to develop and apply multiple novel methods in computational chemistry and is a fervent advocate of joint interactive design sessions between chemists and molecular designers. Martin has coauthored over 60 scientific articles and is an Advisory Board Member of Journal of Medicinal Chemistry. Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data. A Abbreviations: CSD, Cambridge Structural Database; PDB, Protein Data Bank; ITC, isothermal titration calorimetry; MD, molecular dynamics; MUP, mouse major urinary protein; EGFR, epidermal growth factor receptor; MAP, mitogen-activated protein; iNOS, inducible nitric oxide synthetase; PDE10, phosphodiesterase 10; OppA, oligopeptide-binding; DPP-IV, dipeptidylpeptidase IV; LAO, lysine-, arginine-, ornithine-binding protein. And PDB databases. The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility. Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion. The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy. The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule. Like any other spontaneous process, a noncovalent binding event takes place only when it is associated with a negative binding free energy (Δ G), which is the well-known sum of an enthalpic term (Δ H) and an entropic term (− TΔ S). These terms may be of equal or opposite sign and thus lead to various thermodynamic signatures of a binding event, ranging from exothermic to entropy-driven. An increasing body of data from isothermal titration calorimetry (ITC) is available on the thermodynamic profiles for many complexes. Where crystal structure information exists as well, it is tempting to speculate about the link between thermodynamics and geometry of protein−ligand complexes. A rough correlation between the burial of apolar surface area and free energy could be derived, but beyond that, practically useful relationships between structure and the components of free energy have remained elusive. This is not surprising, as both entropy and enthalpy terms obtained from calorimetric experiments contain solute and solvent contributions and thus cannot be interpreted on the basis of structural data alone. The direct experimental estimation of solvent effects has been attempted but always requires additional assumptions. Only theoretical treatments allow a separation of these effects. Thus, computer modeling can support the interpretation of experimental observations.
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