Abstract Details

Rationalization and Visualization of Non-bonded Interactions using Extended Hueckel Theory

Alain Ajamian2, Chris Williams2, Paul Labute2, Simon Grimshaw1
1Chemical Computing Group, St Johns Innovation Centre, Cambridge CB4 0WS, UK
2Chemical Computing Group, 1010 Sherbrooke St. West, Montreal, Quebec H3A 2R7, Canada
Non-standard intermolecular interactions such as CH donors, halogen bonds, close sulphur contacts and cation-pi 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 Hückel 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.

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