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A conformer- and alignment-independent three-dimensional structure−activity relationship (3D-QSAR) model has been derived that is based on flexible molecular interaction fields calculated in GRID and the subsequent description of these fields by use of alignment-independent descriptors derived in ALMOND. The training set consisted of 22 diverse and flexible competitive inhibitors of the drug-metabolizing enzyme CYP2C9 and generated a model with r² of 0.81 and q² of 0.62. The predicitive capacity of the model was externally evaluated with a test set of 12 competitive inhibitors and 11 out of 12 were predicted within 0.5 log unit. The most relevant points of interaction in the model correlated well to the amino acids involved in CYP2C9−substrate/inhibitor binding in the active site of a CYP2C9 homology model, further validating the mechanistic sense of our model.. This approach offers the possibility to derive predicitve 3D-QSAR models without the need for an alignment rule for chemically diverse ligands and in the absence of target protein crystal structure information.

The main purpose of this work is the development and validation of a general scheme based on a systematic and automatic “quasi-flexible” docking approach for studying stereoselective recognition mechanisms. To achieve our goals we explore the conformational and configurational space for small- or medium-size flexible molecules in a systematic way, seeking a method that is both reasonably accurate and relatively fast from the computational point of view. In particular, we have developed a general computational protocol for the global molecular interaction evaluation (“Glob-MolInE”) to efficiently explore the orientational and conformational space of flexible selectors and selectands used in modern chiral high-performance liquid chromatography (HPLC); the enantioselective binding of the selector (S)-N-(3,5-dinitrobenzoyl)-leucine- n-propylamide (S)-1 towards the selectand N-(2-naphthyl)-alanine methyl ester 2 has been studied; the global minimum obtained for the homochiral associate [S(1)/S(2)] (Pop. >99%) is very close (RMS≃0.20) to the crystallographically determined structure. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 515–530, 2000