ORIGINAL RESEARCH An efficient anticancer histone deacetylase inhibitor and its analogues for human HDAC8 Nighat Noureen • Hamid Rashid • Saima Kalsoom Received: 24 June 2010 / Accepted: 12 January 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Histone deacetylase inhibitors (HDACIs) have emerged as efficient chemotherapeutic agents. Molecular docking studies of hydroxamtes, biphenyl and benzamide derivatives using Human HDAC8 with pdb id: 1T69 have been carried out in order to find the most active anticancer HDACI. AutoDock 4.0 has been used for docking. The most active lead compound has been identified on the basis of strong interactions and IC 50 value from the chosen compounds. Five structural analogues have also been designed from the active lead compound. Keywords Histone deacetylase inhibitors Á HDAC8 Á Lead compound Á Human cancers Á Molecular docking Introduction Histone deacetylase inhibitors (HDACIs) represent the promising new class of compounds for the treatment of cancers (Walkinshaw and Yang, 2008). HDAC inhibitors target the gene expression without modifying the DNA sequence. HDAC’s bind DNA tightly to histones thus preventing the transcription of several tumour suppressor genes (Garber, 2004). HDAC inhibitors become potent inducers of growth arrest, apoptosis of transformed cells and differentiation by regulating the gene expression (Fang, 2005). A common set of genes regulated by all HDAC inhibitors was found to be predominantly involved in cell-cycle, apoptosis and DNA synthesis (Glaser et al., 2003). The substrate access is blocked, causing an accu- mulation of acetylated histones when HDAC inhibitors bind directly to the HDAC-active site (Miller et al., 2003). HDACIs comprising of four main structural classes (Walkinshaw and Yang, 2008) including hydroxamates, short-chain fatty acids, benzamides and cyclic tetrapeptides represent a broad family of chemical compounds. These compounds also have distinct affinities for various HDACs along with the structural variations (Walkinshaw and Yang, 2008). Hydroxamic acids are the largest class of HDACIs with great therapeutic potential (Kouraklis et al., 2006). Trichostatin A (TSA) is the first discovered natural product which belongs to hydroxamates group (Yoshida et al., 1990). HDAC8 is the first human protein whose three dimen- sional X-ray crystal structure is widely used in molecular docking studies to reveal the binding properties of HDAC inhibitors (Somoza et al., 2004). Molecular modelling studies have been performed with hydroxamate inhibitors using the crystal structure of HDLP (PDB code: 1C3R) (Chen et al., 2009). The X-ray structural analyses of bac- terial deacetylases, histone deacetylase-like protein (HDLP, PDB entry code: 1C3R) and human HDAC8 have provided researchers macroscopic impression on the binding mode of inhibitors to HDACs (Vannini et al., 2004; Finnin et al., 1999). It was confirmed that the cata- lytic pocket of HDLP structure was highly conserved among all the HDACs, but still there was low sequence or structure similarity among the HDAC classes (Liqin et al., 2009). Most notably there is significant deviation on the enzyme surface, which has a number of shallow pockets adjacent to the deep active site pocket (Somoza et al., N. Noureen (&) Á H. Rashid Department of Bioinformatics, Mohammad Ali Jinnah University, Islamabad, Islamabad Expressway, Near Kaakpul, Kahuta Road, Zone-V, Islamabad, Pakistan e-mail: nighatnoureen@gmail.com S. Kalsoom Department of Chemistry, Quaid-e-Azam University, Islamabad, Pakistan 123 Med Chem Res DOI 10.1007/s00044-011-9571-y MEDICINAL CHEMISTR Y RESEARCH