Since the pioneering effort of Hansch and Fujita, quantitative structure-activity relationships (QSAR) have proved valuable in optimizing lead structures. Enriching classical 3D-QSAR analysis, which exploits the three-dimensional structure of ligands, with structural information of the target has helped to improve the interpretability of the derived models and to increase their predictive power. One such method is the Adaption of Fields for Molecular Comparison (AFMoC) approach where protein-specifically adapted knowledge-based pair-potentials are tailored to one particular protein by considering additional structural and energetic information about ligands. Here, we summarize applications of AFMoC, describe recent developments, and provide an outlook on how to improve the method.
Keywords: Lead optimization; Molecular bioinformatics; Protein flexibility; Scoring function; Structureactivity relationship.
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