Histone deacetylases (HDACs) are a family of enzymes involved in gene expression and post-translational modifications. HDACs are very important targets for drug development due to their roles in cancer and other diseases. Several HDAC inhibitors have been developed, however, many known inhibitors produce side-effects because of their poor selectivity. This paper presents a striking example of how state-of-the-art QM/MM-MD calculations can be used for computer-aided drug design (CADD).
Based on their previous calculations on the mechanism of the wild-type enzyme, Zhou and co-workers hypothesized that a selective inhibitor could be created by developing a molecule that would undergo an HDAC-catalyzed intra-molecular reaction. To this end, the authors proposed several candidates and used QM/MM-MD simulations to study the mechanism in gas-phase, solution and in the enzyme active site. The most promising candidates ( –hydroxymethyl and –aminomethyl substituted chalcones) were subsequently synthesized and characterized in vivo. The authors further analyzed the mechanism of inhibition via QM/MM-MD for the most promising candidate to understand how this molecule acts as an HDAC2-selective, time-dependent inhibitor.
Reprinted with permission from ACS Chem. Biol., Article ASAP DOI: 10.1021/cb500767c . Copyright (2014) American Chemical Society.