Dynamic QSAR techniques: applications in drug design and toxicology

The basic principles of 3-D quantitative structure-activity relationships (QSARs) analysis are discussed in the light of the fuzzy logic concept. According to that concept, the traditionally one chemical - one structure - one parameter value relationship in QSAR is suggested to be modified into one chemical finite set of structures - range of parameter values principle. In this respect, two recently developed techniques accounting for conformational flexibility in 3-D QSARs are reviewed. A basic assumption underlying both methods is that chemical behavior in complex biological systems is context-dependent. A molecule can exist and interact in a variety of conformations depending on the specificity of the endpoint under investigation and reaction media. It was demonstrated that selection of active conformer(s) in QSAR studies is a task as important as the selection of relevant molecular parameters. Specifically selected active conformers, rather than the lowest-energy states of the chemicals are suggested to be used in the correlative QSARs. The method for recognition the common reactivity pattern (COREPA) of structurally heterogeneous compounds that elicit similar biological behaviour is based on all energetically reasonable conformers of chemicals. The principle assumption of the method is that biologically similar chemicals should possess a commonality in their stereoelectronic (reactivity) pattern. Originally developed algorithms for conformer generation are presented in association with the QSAR methods accounting for conformational flexibility of chemicals. Applicability of the QSAR technique for selection active conformers is illustrated by presenting QSAR models derived for Ah binding affinity of PCBs and antimicrobial activity of rifamicin derivatives. Models for predicting estrogenic activity of structurally diverse chemicals and ACE inhibition exemplified the applicability of the COREPA method. The model performance is analyzed by the 3D screening exercise of large chemical inventories with subsequent experimental validation within the EDAEP project. Besides the impact of conformational flexibility of chemicals in 3D QSAR the role of different molecular descriptors is discussed with respect to their ability to describe molecular interactions with different specificity.