Development of the selective Histone Deacetylase (HDAC) inhibitors remains a significant challenge due to highly structural similarity among the 11 zinc-dependent HDAC isoforms. Among the HDAC isoforms, it is particularly difficult to achieve isoform inhibition selectivity between HDAC1 and HDAC2, since they share a very high sequence similarity (97.8%), have the same conserved residues around the catalytic pocket, and the RMSD of two aligned protein crystal structures is only 0.7 Å. As a result, it has been very challenging to develop an HDAC2 selective inhibitor by employing conventional structure-based or ligand-based drug design approaches. Herein, I will share a story on how to use the Quantum Mechanics/Molecular Mechanics (QM/MM) calculation and experimental validation to design a time-dependent HDAC2-selective inhibitor, β-hydroxymethylchalcone, by taking advantage of the enzymatic reactivity difference.
Lecturer: Wu Ruibo, Professor, Sun Yat-sen University.
Venue: Room 426, Zhuangjin Building