Identification and rationalization of non-standard interactions presents many challenges during optimization of lead drug candidates. The typical approach of using SMARTS patterns to handle CH...O interactions is impractical as it requires a large set of patterns. An additional degree of difficulty is introduced when considering moieties such as halogen bonds, proton-p interactions, sulfur-aromatic and the like. In order to address these challenges, Extended H�ckel Theory (EHT) is used to handle and account for the fundamentals of electron-withdrawal effects in relation to non-standard and hydrogen bond interactions. The EHT approach to modeling non-standard non-bonded interactions uses partial charges and bond orders from extended Huckel theory (EHT) to derive interaction strength parameters. Furthermore, it accounts for resonance and electron withdrawal effects in a true QM fashion, circumventing the need to encode subtle electronic differences with a myriad of SMARTS matches and atom types, which is typically used in most force-field calculations. Applying the EHT method is especially useful when dealing with CH donors, whose strengths are greatly influenced by local resonance and electron withdrawal. The Huckel strength parameters are interesting by themselves as input to QSPR equations, as they correlate well with physio-chemical properties such as solvation energy and pKa. Given that the EHT based non-bonded interaction model is a molecular orbital-based Lewis Acid/Lewis Base approach, it naturally extends to all manner of non-bonded interactions - CH donors, sulfur-O contacts, cation-pi, and H-pi interactions - and contrasts point-charge based methods, which cannot deal with the anisotropic charge distributions that give rise to many non-standard interactions. Here we also demonstrate the quantitative accuracy of our model, by showing how our computed halogen-bond energies correlate well with experimental activity differences in a congeneric series of halogenated ligands. The ability to better quantify non-standard non-bonded interaction strengths provides the opportunity to better predict and assess these interactions for explaining existing SAR, and to exploit these interactions in ligand design. Current non-standard interaction models do not consider the halogen bond interaction, and instead see it as a VDW clash. Using such models would be detrimental and potentially misleading in situations where the halogen bond contributes to ligand binding affinity. Our new framework for non-standard interactions is a step towards their inclusion in SBDD projects and in the medicinal and computational chemistry arsenal of modeling applications.

Exploring the duality of halogens as participants in non-bonded interactions during lead optimization

248th National Meeting (2014)

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