Quantum chemical calculations coupled to experiments were used to predict covalent hydration propensities of biologically-relevant α-ketoamides. As a starting point, computationally determined hydration equilibrium constants for related ketones and aldehydes were correlated to experimentally determined values resulting in a method for predicting hydration equilibrium constants. Applying our method to a test set of six α-ketoamides revealed a correlation between computationally predicted and experimental equilibrium values for hydration. This correlation was applied to several germane APIs, and our results indicate that the keto form is favored for practically all of these α-ketoamides in biological environs. While many steps in this work are accessible to the blind, one step required conformational searching using software that, unfortunately, is inaccessible. HBW, a co-author on this project, is completely blind, and the focus of this presentation is the development of accessible computational methods to close this gap. The centerpiece of this approach is a 2-dimensional, 360-degree dihedral scan employed to determine the lowest energy conformation of the hydrate form (a geminal diol functional group). This accessible protocol has the potential to replace the inaccessible conformational search, and the results thus obtained were applied to several of our newly synthesized α-ketoamides.

Blind and visually impaired-accessible investigation of hydration propensities of biologically relevant α-ketoamides

251st National Meeting (2016)

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