Non-standard intermolecular interactions such as CH donors, halogen bonds, close sulfur contacts and cation-p interactions have recently been recognized as significant factors in protein-ligand binding. However, exploiting these interactions in structure-based drug design projects (SBDD) has been difficult, because they are inadequately modeled using MM force-field based methods. Atom-centered charges typically used in force-fields cannot capture the anisotropic charge distributions responsible for some non-standard interactions. To address these challenges, a model of intermolecular interactions based on Extended H�ckel Theory (EHT) is proposed, which accounts for the effect of electron delocalization and geometry on interaction strength. The qualitative and semi-quantitative accuracy of the model is demonstrated using case studies that highlight the importance of non-standard interactions in a number of systems, including native ligands of the thyroid hormone receptor.

Rationalizing non-standard interactions in ligand design: The duality of halogens

245th National Meeting (2013)

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