Molecular alignment is a key procedure for measurements of the 3D similarity between compounds, pharmacophore elucidation or QSAR analysis. Several factors influence alignment quality, including the quality of the physico-chemical descriptors utilized to account for the molecular determinants of biological activity. Relying on the hypothesis that the variation in maximal achievable binding affinity for an optimized drug-like molecule is largely due to desolvation, we explore here a novel strategy for the 3D alignment of small molecule that exploits the partitioning of molecular hydrophobicity into atomic contributions in conjunction with information about the distribution of hydrogen-bond donor /acceptor groups in each compound. A brief description of the method, as implemented in the software package PharmScreen, including discussion on the calculation of the fractional hydrophobic contributions within the quantum mechanical version of the MST continuum method, and the procedure utilized for searching of the optimal superposition between molecules, is presented. The computational procedure is calibrated by using a dataset of 402 molecules pertaining to 14 distinct targets taken from the literature, and validated against the AstraZeneca test set of 1456 crystal structures from 121 different receptors. The results confirm the suitability of MST based-hydrophobic parameters for generating molecular overlays with correct predictions obtained for 100%, 93%, 55% and 12.5% of the molecules classified into easy, moderate, hard and unfeasible sets, respectively.

Hydrophobic similarity between molecules: Application to three-dimensional molecular overlays with PharmScreen

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.