Pharmacophore models play an essential role in drug discovery. Generating pharmacophore models which encode accurate molecular recognition features are highly dependent on properly defined annotation points. Simplistic or ill-defined pharmacophore annotations which do not capture subtle electronic or geometric effects lead to many inaccuracies. “Rule” based methods which typically employ SMARTS patterns to specify annotation "rules" are subject to such inaccuracies. Here we  have developed a new approach for pharmacophore modeling which is based on a semi-empirical method using Extended Hückel Theory (EHT). In contrast to “rule” based approaches, the EHT method uses a model to assign annotation points and generate features. The pharmacophore features generated through the EHT annotation scheme take into account ligand resonance and electron withdrawing effects and are sensitive to non-standard interactions, such as C-H and halogen bond interactions, during pharmacophore screening.

Applying extended Hückel theory to pharmacophore modeling

251st National Meeting (2016)

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