ChemBioChem 2003, 4, 1249 ± 1252 www.chembiochem.org ¹ 2003 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 1249

Protein ± Ligand Interactions–From Molecular Recognition toDrug Design MethodsEdited by Hans-Joachim Bˆhm and GisbertSchneider

Wiley-VCH, Weinheim 2003. XX� 242 pp. , hardcover� 129.00.–ISBN 3-527-30521-1

™Protein ± Ligand Interactions∫ is Vol-ume 19 in the Wiley-VCH series. It is atimely review ofmolecular recog-nition events be-tween proteinsand small mole-cule ligands inaqueous mileu,the understand-ing of whichforms the funda-mental basis ofmedicinal chemis-try. I will not hold you, the reader, insuspense for the next 1200 words, I didlike this nice little book, although it couldhave benefitted from being a nice bigbook. I do recommend you read it.The editors have assembled an author-

itative group of authors to present in ninechapters an overview of selected themesfrom the general area of protein ± ligandinteractions.Chapter 1 begins by describing ap-

proaches to predict the sum contributionof ligand±protein interactions to theoverall binding affinity of a ligand orseries of ligands to a protein target. Thechapter contains terse descriptions offorcefield-based methods, empirical scor-ing functions, and so-called knowledgebased methods for predicting bindingfree energy. Some of the limitations ofcurrent scoring functions are also descri-bed, together with citations to successfulexamples of the application of scoringfunctions in virtual screening and De no-vo Design.Chapter 2 jumps to the study of host ±

guest complexation, or supramolecular

chemistry. At first this seems somewhatout of place, but by the end of thechapter the sense in its placement be-comes clear. Measurements with synthet-ic host ±guest systems allow detaileddissection of key interactions in molecularrecognition, which can be directly appliedto more complex biological systems.Within the framework of host ±guestchemistry a number of key concepts areintroduced, including the chelate effect,strain, solvent effects, enthalpy ± entropycompensation, the role of flexibility- andinduced fit, amongst others.Experimental approaches to determine

the thermodynamics of protein ± ligandinteractions are described in Chapter 3. Avery brief but well-written description ofclassical thermodynamics is given, neces-sary to reach the definition of Gibbs freeenergy. The rest of the chapter largelydescribes the application of microca-lorimetry and the Vant ±Hoff method tothe determination of thermodynamic pa-rameters.The biophore or pharmacophore con-

cept is described in Chapter 4. The con-cept of the pharmacophore is an abstrac-tion of the fundamental forces underlyingmolecular recognition. It is an abstractionthat embeds these thermodynamic con-cepts into a simple geometrical modelunderstandable for a medicinal chemist,and hence their computer algorithms.The definition of pharmacophores is anunderlying principle of medicinal chem-istry that allows rational scaffold hopping,patent busting, and lead optimization ingeneral, but in recent years pharmaco-phores have allowed the automatedsearching of real or virtual compounddatabases, as a supplement or replace-ment for large-scale screening in leadidentification.Chapter 5 describes the study of drug ±

receptor interactions for membrane-bound receptors, and technologies thatcan be used to help refine G-protein-coupled-receptor models in the absenceof crystallographic structural data. The

chapter starts with a brief description ofassay technologies for the determinationof binding constants, followed by ligandstructure ± activity data. The use of anti-bodies to map the location of ligandbinding sites is described, as is the use ofaptamers, RNA, or DNA molecules gen-erated by evolutionary synthetic enriche-ment, to recognize small molecules, pep-tides, or proteins. Finally the contributionof mutagenesis to our understanding ofdrug ± receptor interactions is describedtogether with the use of photactivatablegroups to identify ligand binding sites.Chapter 6 describes the role of hydro-

gen bonds in protein ± ligand complexes.It contains some classic citations on thesubject and if one ever required a ™bluff-ers guide to hydrogen bonding∫, this is it.The role of water is rightly given specialattention, although the garden-hose/wa-tering-can approach to the addition ofwater molecules to X-ray crystal struc-tures in the refinement process may addan additional ambiguity to some of theconclusions based on crystallographicobservations. Chapter 7 describes theprinciples of enzyme± inhibitor designand applies the principles described inChapters 1 ± 6 to drug design.Chapter 8 takes another interesting

turn, as it applies the principles of molec-ular recognition to the tailoring of proteinscaffolds to recognize new ligands. Lipo-calins are �-barrel folds capped at oneend, with hypervariable loops at the openend. Site-directed random mutations in-duced in the hypervariable loops lead tolarge protein libraries that offer an oppor-tunity to study ligand ±protein interac-tions from the protein point of view.The final chapter describes a number of

lead-finding techniques, often called af-finity screening methods. These methodsare complimentary to high-throughputscreening (HTS), as they can identifyspecific binders in the tens of millimolarto millimolar range±out of range for mostHTS screens. The chapter focuses uponsmall-molecule screening on chemical

Drugs: Designed, Sealed and Delivered

1250 ¹ 2003 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim www.chembiochem.org ChemBioChem 2003, 4, 1249 ± 1252

microarrays, the basis of screening tech-nology at Graffinity Pharmaceuticals.In some sense the editors of the book

appear confused as to its intended read-ership. Some chapters start from a verybasic level for the average medicinalchemist and are more suited to an under-graduate text. Others are of interest evento those well-versed in the field, eitherbecause of the interestingly differentslant taken on the subject, or just as aresult of the valuable collection of cita-tions in a familiar area, which gives foodfor thought and further reading. Forinstance, deductions from the design ofhosts for small-molecule ligands, or fromthe evolutionary design of artificial re-ceptors, are of direct relevance to medic-inal chemistry. But these areas are prob-ably on the periphery of the core brows-ing for most medicinal chemists. Somaybe this book does succeed in beingall things to all people.Many interesting and provocative facts

and observations cited throughout thebook would have benefited from furtherdevelopment. The book could justifiablyhave been longer. The nonclassical pro-tein ± ligand interactions, such as �± ca-tion interactions and C±H hydrogenbonds could have been further discussed.Hydrophobicity as a key determinant ofmolecular recognition, or the role ofwater in drug ± receptor interactions, arenot given their own chapters, and the roleof protein flexibility is only sporadicallymentioned. An extended chapter on thethermodynamics of drug± ligand interac-tions would have been valuable. The areaof protein ± ligand interactions for sub-strates and inhibitors of metabolic en-zymes and transport processes is men-tioned in David Brown's prologue, butthese themes never appear again. Hencemy conclusion that this is a nice littlebook but could have been a nicer bigbook. The book was still very enjoyable.My favourite chapter was David Banner'sChapter 7, which describes the principlesof enzyme inhibition. While this chapterprimarily covers Banner's experience withthrombin, he highlights wider implica-tions of many of his conclusions. Bannergives many useful tit-bits of guidancethroughout his chapter, which eitherstem from deep insight, or hard-bittenexperience, or both. These include ™ex-

pect the unexpected∫, ™the tail does notwag the dog∫, protein flexibility is oftenoverlooked, inhibitors and protein do notalways bind in their lowest energy con-formation, selectivity between isoformsmay not just be dependent upon activesite residues, but also residues out in thesecond shell from the active site. Finallyhe suggests the best approach is to ™tryto extract helpful (structure ± activity rela-tionship) rules from the available data,but be prepared to break them. This issound advice indeed, Dr Banner, wesalute you.The book is produced to a high stan-

dard, as we have come to expect fromWiley-VCH. Having reached middle agerecently, together with waistline and hair-line, my eyesight is becoming more™relaxed∫. Hence, reading this book infront of late-night television, or whilewaiting for my daughters in their danceschool cafe¬ , I wished for a larger fontsize,a darker font or both. But for those youngerreaders, or readers with better opticiansthan mine, I recommend this book.

Andy DavisDepartment of Medicinal ChemistryAstra Charnwood, Loughborough (UK)

Biomimetic Materials and De-sign: Biointerfacial Strategies,Tissue Engineering, and Tar-geted Drug DeliveryEdited by Angela K. Dillow and Anthony M.Lowman.

Marcel Dekker, Inc. , New York 2002. 696 pp. , hard-cover $ 195.00.± ± ISBN 0-8247-0791-5

Once driven by the need for biocompat-ible, bioinert materials for orthopedic anddental applications, research in biomate-rials is now focused on developing bio-mimetic materials that are tailored forspecific interactions with biological mac-romolecules, cells, and tissues. Based inthe large part on the need for newmaterials for tissue engineering and drugdelivery applications, this philosophicalparadigm shift is woven throughout thebook entitled, Biomimetic Materials andDesign: Biointerfacial Strategies, Tissue En-gineering, and Targeted Drug Delivery.

Despite a plethora of recent researchreview textbooks covering each of thesetopics individually, this text presents arefreshing, concise, and timely treatmentof the important concepts and principlesthat unify these areas. Engineers, materi-als scientists, chemists, and cell biologistsworking in these areas will undoubtedlyappreciate this book.The book begins with a brief preface

from the editors, who provide an excel-lent synopsis of the field and its short-comings, which explains the motivationfor the choice of topics covered in theindividual chapters. The chapters presentan exciting blend of contributions fromthe pioneers in this field (Drs. Langer,Peppas, Tirrell, and Hoffman), provenexperts (Drs. Healy, Matthew, Schmidt,and West), and up-and-coming younginvestigators (Drs. Garcia, Shea, and Car-beck). The topics are divided into threeseparate but related areas: Biointerfacialstrategies (Chapters 1 ± 7), tissue engi-neering (Chapters 8 ± 13), and targeteddrug delivery (Chapters 14 ± 19). Like allbooks of this type, there is clearly someredundancy in the material covered ineach individual chapter. However, theattempt of the editors to unify thesechapters by using three centralized the-matic areas works quite well.For those of us working at the interface

between cells and the extracellular ma-trix, the first section's treatment of celladhesion-dependent signaling and thepresentation of various strategies to con-trol these signals is provocative, thor-ough, and informative. Turning backtowards the basic sciences captures theaforementioned paradigm shift shapingthe advancement of biomaterials, onethat is particularly evident in these chap-ters as the authors have an obviousappreciation for the mechanisms bywhich cells interact at interfaces. How-ever, an understanding of these mecha-nisms and the ability to manipulate themremains perhaps the most significantchallenge to the advancement of thisfield.Efforts to exploit these biointerfacial

strategies for tissue engineering applica-tions are covered in the next section ofthe book. Tissue engineering research hasprimarily focused on the adaptation ofexisting polymers and the development