Structure-based modeling of histone deacetylases inhibitors

Macromolecules (proteins, nucleic acids and polysaccharides) three-dimensional (3-D) structures obtained by either X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy are of a prominent role in the drug discovery (DD) process (Figure 1). In the latter some boost was received from the inclusion of rapid synthetic procedures of combinatorial chemistry (Mjalli & Harris, 1996) and the elegance of rational library design (Matter, Baringhaus, Naumann, Klabunde, & Pirard, 2001). The prosperity of computational methods which explore both the receptor structure (structure based approaches, SB) and ligand based approaches like pharmacophore modeling (Langer, 2010) and 3-D quantitative structure-activity relationships (3-D QSAR) (ligand based approaches, LB) (Doweyko, 2006), provide novel opportunities for chemists to discover new lead compounds by either synthetic efforts stage (gray lane) or high throughput virtual screening of huge compounds libraries using SB or LB based approaches (brown flow, Figure 1). In the lead optimization iterative protocol, SBDD represent the top technique that during the drug discovery processes is seek to be pursued. In this scenario, the design process can have different starting points upon the availability of either the target structure or known ligands (Figure 2). In 1999 Finnin et al reported the first structure of a histone deacetylase like protein (HDLP) co-crystallized with suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) that prompted a numerous researchers to start SBDD studies in the epigenetic field. Rome Center for Molecular Design (RCMD) lab was among the first to report those kind of studies that after more than 15 years are still ongoing due to the enormous amount of data continuously released on HDACs. This chapter focuses on SBDD approaches on histone deacetylase (HDAC) inhibitors (HDACi) that were applied by the RCMD lab. This report covers mainly Zn-based HDACi, although some studies on NAD-based HDAC (Sirtuin) inhibitors are also included at the bottom of the chapter.