version date: 1 December 2006 analogy may not necessarily be conserved over a wide range of molecules even with regard to a single biological parameter. Nevertheless, the concept of interchangeable groups which are poten- tially bioanalogous with regard to a single or many biological parameter(s) is indisputably very sefuL. Indeed, for the medicinal chemist, the greatest potential of the concept lies in systematic searching of a database to find group replacements which, starting from a lead molecule, could ield novel or useful active molecules The term"isostere"is so widespread that it can be maintained and continue to be used but only with regard to structure. It should, however, be redefined to be consistent with the current meaning of the adjective steric. Thus, isosteric literally means identical in size and shape but to be useful isosteric must be subjectively defined to mean similar in size and shape. with this classification, the terms"isosteric"and"non-isosteric bioanalogs"were proposed(Floersheim et al., 1992)to replace the terms"classical and "nonclassical bioisosteres'' Any consideration of isosterism has to take conformational parameters into account. Clearly, two conformations of the same molecule will not necessarily be isosteric; both, however, may be bioanalogous, if they can elicit similar biological activity Thus, it must be considered whether a chemical modification of a compound affects its confor- mational preferences, and through this mechanism, its biological activity. An additional difficulty may arise in attempting to relate molecules with analogous biological activity when racemic mix tures are used. As has been amply recognized by others, enantiomers interacting with chiral bio- molecules may differ greatly in their activities. Enantiomers are not isosteric, as they are by definition non-superimposable, but they may be bioanalogous. This is in agreement with pfeiffe rule, which refers to the generalization that the greater the biological activity of the racemate, the larger the difference in the activity of the enantiomers. This could be interpreted as the effect of a closer interaction between each of the enantiomers and the receptor, enhancing the stereodifferen- tiation. In other cases, however, Pfeiffers rule does not hold In conclusion, for constructing structure-activity relationships where biological activity is a consequence of a molecular recognition process, while certain empiricisms may be useful, struc- tural considerations grounded in first principles are of prime importance. Thus, isosterism, carefully defined on purely structural considerations, may point the way to bioanalogous molecules with a desirable pharmacological profile Floersheim P, Pombo-Villar E, Shapiro, G. Isosterism and Bioisosterism Case Studies with Muscarinic Agonists", Chimia 46, 323-334 (1992)and references cited therein Material and methods Molecular mechanics calculations and quantum chemical calculations play a multiple role in mod- ern-day computational chemistry. Molecular mechanics calculations on complex molecules may even be performed on personal computers and have spread widely throughout the chemical com- munity Quantum chemical calculations, even semiempirical molecular orbital calculations, but es- pecially ab initio molecular orbital calculations and density functional calculations, are much more time-demanding. Recently, with the availability of fast workstations and efficient graphics-based programs, these methods have begun to be widely applied Quantum chemical methods are also useful for furnishing information about the mechanism and product distributions of chemical reactions, either directly by calculations on transition states, or indirectly by modeling the steric and electronic demands of the reactants. Quantum chemical calculations are also able to supply information needed as input for other techniques, for example, atomic charges for QSAR analyses. Ab initio Hartree-Fock and correlated molecular orbital calcu lations, and density functional calculations are also able to provide accurate intra- and interno- lecular potentials. This kind of information is required both by molecular mechanics and by molecular dynamics techniques used to describe a wide variety of phenomena, ranging from inter actions between an enzyme and a drug to the physical properties of polymeric materials <www.iupac.org/publ ns/cd/medicinal chemistry/>5 analogy may not necessarily be conserved over a wide range of molecules even with regard to a single biological parameter. Nevertheless, the concept of interchangeable groups which are poten￾tially bioanalogous with regard to a single or many biological parameter(s) is indisputably very useful. Indeed, for the medicinal chemist, the greatest potential of the concept lies in systematic searching of a database to find group replacements which, starting from a lead molecule, could yield novel or useful active molecules. The term “isostere” is so widespread that it can be maintained and continue to be used but only with regard to structure. It should, however, be redefined to be consistent with the current meaning of the adjective steric. Thus, isosteric literally means identical in size and shape, but to be useful, isosteric must be subjectively defined to mean similar in size and shape. With this classification, the terms “isosteric” and “non-isosteric bioanalogs” were proposed (Floersheim et al., 1992) to replace the terms “classical” and “nonclassical bioisosteres”. Any consideration of isosterism has to take conformational parameters into account. Clearly, two conformations of the same molecule will not necessarily be isosteric; both, however, may be bioanalogous, if they can elicit similar biological activity. Thus, it must be considered whether a chemical modification of a compound affects its confor￾mational preferences, and through this mechanism, its biological activity. An additional difficulty may arise in attempting to relate molecules with analogous biological activity when racemic mix￾tures are used. As has been amply recognized by others, enantiomers interacting with chiral bio￾molecules may differ greatly in their activities. Enantiomers are not isosteric, as they are by definition non-superimposable, but they may be bioanalogous. This is in agreement with Pfeiffer’s rule, which refers to the generalization that the greater the biological activity of the racemate, the larger the difference in the activity of the enantiomers. This could be interpreted as the effect of a closer interaction between each of the enantiomers and the receptor, enhancing the stereodifferen￾tiation. In other cases, however, Pfeiffer’s rule does not hold. In conclusion, for constructing structure–activity relationships where biological activity is a consequence of a molecular recognition process, while certain empiricisms may be useful, struc￾tural considerations grounded in first principles are of prime importance. Thus, isosterism, carefully defined on purely structural considerations, may point the way to bioanalogous molecules with a desirable pharmacological profile. • Floersheim P., Pombo-Villar E., Shapiro, G. “Isosterism and Bioisosterism Case Studies with Muscarinic Agonists”, Chimia 46, 323–334 (1992) and references cited therein. Material and Methods Molecular mechanics calculations and quantum chemical calculations play a multiple role in mod￾ern-day computational chemistry. Molecular mechanics calculations on complex molecules may even be performed on personal computers and have spread widely throughout the chemical com￾munity. Quantum chemical calculations, even semiempirical molecular orbital calculations, but es￾pecially ab initio molecular orbital calculations and density functional calculations, are much more time-demanding. Recently, with the availability of fast workstations and efficient graphics-based programs, these methods have begun to be widely applied. Quantum chemical methods are also useful for furnishing information about the mechanisms and product distributions of chemical reactions, either directly by calculations on transition states, or indirectly by modeling the steric and electronic demands of the reactants. Quantum chemical calculations are also able to supply information needed as input for other techniques, for example, atomic charges for QSAR analyses. Ab initio Hartree–Fock and correlated molecular orbital calcu￾lations, and density functional calculations are also able to provide accurate intra- and intermo￾lecular potentials. This kind of information is required both by molecular mechanics and by molecular dynamics techniques used to describe a wide variety of phenomena, ranging from inter￾actions between an enzyme and a drug to the physical properties of polymeric materials. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006