Kinetic barriers in the isomerization of substituted ureas: implications for computer-aided drug design

Urea derivatives are ubiquitously found in many chemical disciplines. N,N′-substituted ureas may show different conformational preferences depending on their substitution pattern. The high energetic barrier for isomerization of the cis and trans state poses additional challenges on computational simulation techniques aiming at a reproduction of the biological properties of urea derivatives. Herein, we investigate energetics of urea conformations and their interconversion using a broad spectrum of methodologies ranging from data mining, via quantum chemistry to molecular dynamics simulation and free energy calculations. We find that the inversion of urea conformations is inherently slow and beyond the time scale of typical simulation protocols. Therefore, extra care needs to be taken by computational chemists to work with appropriate model systems. We find that both knowledge-driven approaches as well as physics-based methods may guide molecular modelers towards accurate starting structures for expensive calculations to ensure that conformations of urea derivatives are modeled as adequately as possible. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-016-9913-4) contains supplementary material, which is available to authorized users.