Dynamic QSAR: A New Search for Active Conformations and Significant Stereoelectronic Indices

Abstract

A new approach called "dynamic" QSAR is introduced to enhance the exploration of active chemicals and relevant molecular descriptors. In contrast to conventional QSAR methods where chemical structure is described by a single, low energy conformer, "dynamic" QSAR simulates the multiplicity of 3-D molecular shapes that a molecule can assume in complex reaction environments. The core of the new methodology is the coupling of the 3DGEN algorithm which exhaustively generates conformers and a rule-based system to rapidly screen conformers for desired properties. Hypotheses regarding receptor shape and interaction mechanisms are conveniently incorporated into the screening algorithm. A full array of stereoelectronic parameters available to OASIS can be combined with conventional topological and physicochemical indices for all conformations and explored using a variety of mathematical and visualization techniques. The "dynamic" QSAR method is illustrated by modeling the acute toxicity of a series of unsaturated alcohols in fish.After some modifications. other 3D modeling packages (e.g., WI-ZARD) can also be suitable for employing dynamic QSAR analysis. However, a problem here is the fact that the existing conformer generators are based on the exploring conformational space

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

“…As opposed to conventional QSAR methods, the approach used in this study does not assume a priori that 3-D molecular structures represented by single lowest-energy gas-phase conformers are appropriate to model physicochemical properties, toxicological end points, or the interactions of xenobiotics with receptors in a solvated environment [21,33,34]. Use of this method permits a systematic assessment of the conformational space associated with the compounds of interest, either in the context of testing specific hypotheses or as a means of exploring possible ligandreceptor interactions.…”

“…Based on the assumption that conformational flexibility is of critical importance in ligand-receptor interactions, we employed a dynamic QSAR method [21] to model the relative ER binding affinity of a series of PCHBs. As opposed to conventional QSAR methods, the approach used in this study does not assume a priori that 3-D molecular structures represented by single lowest-energy gas-phase conformers are appropriate to model physicochemical properties, toxicological end points, or the interactions of xenobiotics with receptors in a solvated environment [21,33,34].…”

“…The identification of proposed ''active'' conformers was based on an evaluation of the regression statistics associated with QSARs derived using the different conformation samples. Recent dynamic QSAR studies on the toxicity of unsaturated alcohols [21], semicarbazides [33], and ␣-terthienyls [34], as well as the binding of PCBs to the Ah receptor (O.G. Mekenyan et al, unpublished manuscript), indicated that models based on nonoptimized conformer geometries were not qualitatively different from those based on optimized structures.…”

“…Using the OASIS system [22,23], the dynamic QSAR method combines an exhaustive conformer generation routine [24] with conformer screening algorithms that can be adapted to explore relationships between specific electronic properties and the biological activity under investigation [21]. The conformer generation technique is described by Ivanov et al [24], and the reader is encouraged to consult this reference for a detailed presentation of the approach.…”

“…However, in some instances, the most stable conformations may be the least likely to interact with a solvent or macromolecule [20]. To systematically evaluate conformer flexibility within the context of relevant biological environments and reactions (e.g., partitioning within a complex solution, substrate-receptor complex formation, and subsequent electronic interactions), a ''dynamic'' QSAR approach was incorporated in the present study [21]. The method assumes that in the complex reaction environments of biological systems a molecule can exist as a variety of conformers, with solvation and binding interactions compensating for energy differences among the conformations.…”