Review Special F ocuS: computational chemiStRy Chemodiversity & its meaning Chemodiversity begins with the simplest chemi- cal objects, namely atoms. Indeed, there is some electronic diversity in a given atom, since it has a number of electronic states available depending on ionization and occupation of atomic orbit- als. However, genuine geometric states emerge at the level of molecules, where conformational states, mainly, and tautomeric states, occasion- ally, dramatically expand the property space open to molecules compared with atoms [1,2] . As is well known, a given molecule can exist as a number of conformers. To use a metaphor, a molecule is a ballerina and not a statue. In plain terms, the 3D-geometry of a molecule fluctu- ates within its energy-allowed range [3,4] , thus, defining a conformational space that comprises all the microstates energetically accessible to the molecule. These states are snapshots of the mol- ecule at a given moment in time and they are characterized by a definable form. The confor- mational space delineated by all conformers of a molecule can be seen as its basin of attraction [5,6] or an energy landscape [7] , namely a hypersurface whose dimensions are the energy of the system, plus all its geometric variables. Considering the described molecular variabil- ity, it comes as no surprise that a detailed ana- lysis of molecular flexibility for both ligand and receptor is now usually taken into account, with a view to enhancing the classical static drug-design methodologies. Modern docking programs rou- tinely account for ligand flexibility as well as receptor flexibility, which can be modelled con- sidering both conformational changes at a mac- romolecular level and small variations involving one or a few residues. The former is generally due to domain rearrangements and can be accounted for by multiple protein structures obtained exper- imentally or by in silico techniques, whereas the latter is due to side chain flexibility and can be simulated by exploiting rotamer libraries [8] . Similarly, pharmacophore mapping greatly ben- efits from an assessment of flexibility since the flexible superimposition of biologically active molecules is a crucial step in similarity analysis and, hence, in ligand-based drug design [9] . In addition, quantitative structure–activity relation- ship (QSAR) analyses have evolved towards mul- tidimensional approaches, which consider both the three-dimensional structures (3D-QSARs) and their flexibility (nD-QSARs) [10] . Chemodiversity and molecular plasticity: recognition processes as explored by property spaces In the last few years, a need to account for molecular fexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a fexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defnes a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure–activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fll this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences. Giulio Vistoli †1 , Alessandro Pedretti 1 & Bernard Testa 2 1 Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, Facoltà di Farmacia, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133 Milano, Italy 2 Department of Pharmacy, University Hospital Centre, Rue du Bugnon, CH-1011 Lausanne, Switzerland † Author for correspondence: Tel.: +39 025 031 9349 Fax: +39 025 031 9359 E-mail: Giulio.Vistoli@unimi.it 995 ISSN 1756-8919 Future Med. Chem. (2011) 3(8), 995–1010 10.4155/FMC.11.54 © 2011 Future Science Ltd For reprint orders, please contact reprints@future-science.com