REMER Talks / Application of Computer-Based Methods to Guide the Development of NovelSirtuin Inhibitors

12 April 2017, at 2 o’clock, Berin Karaman from Université Paris Descartes is going to be at REMER Seminar Room.

What about topic of seminar?

Silent information regulator 2 (Sir2) proteins, also named sirtuins (SIRTs) are promising therapeutic targets which have been linked to the pathogenesis of several diseases including metabolic disorders, neurodegeneration and cancer. During the last decade designing sirtuin modulators with drug like properties has spurred great interest. However, most of these compounds showed limited potency and isoform selectivity.
In the current work, we established the structural basis of Sirt2-selective inhibition with a novel potent drug-like inhibitor named SirReal2. Crystal structures of Sirt2 in complex with SirReal2 revealed a ligand-induced rearrangement of the active site and formation of a yet-unexploited allosteric binding pocket. In order to rationalize the SirReal2-mediated high-subtype selectivity, we performed sequence and structural alignments within the members of sirtuin family. We generated homology models and carried out docking studies of SirReal2 to get insights into the isoform-selective inhibition mechanism of this compound. Based on the obtained results, we demonstrate that the residues that form the SirReal2 binding pocket differ significantly within the sirtuin family and minor sequence variations in the catalytic pocket hamper the correct orientation of SirReal2. This newly identified pocket can be targeted to design selective Sirt2 inhibitors in the future [1].
Next, we developed a post-docking filter- an MM-GBSA protocol – for structure-based optimization of sirtuin inhibitors. We showed that protein-inhibitor complexes of sirtuin isoforms can be produced by means of ligand docking and applying a short molecular dynamics (MD) simulation. This method is faster and less complex than applications such as homology modeling which requires expertise. Moreover, this method can also be applied to other protein targets beside sirtuins. A significant correlation is determined between the binding free energy of the compounds estimated by MM-GBSA calculations and experimental data. The established MM-GBSA protocol is computationally inexpensive and can be applied as a post-docking filter in virtual screening campaigns to identify novel sirtuin inhibitors [2].