Speaker
Mr
Cvijetić Ilija N.
(Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski Trg 12-16, Belgrade)
Description
Acetylation and deacetylation of histone is an important mechanism to regulate the DNA expression. Two main classes of enzymes catalyze this regulatory mechanism: histone acetyltransferase (HAT) and histone deacetylase (HDAC). HDACs are involved in signal transduction, cell growth and cancer [1]. We report the results of the preliminary ligand-based virtual screening in the search of the novel HDAC-1 inhibitors. By this virtual screening study, we aimed to test the performances of the OpenEye applications installed on our home cluster PARADOX. As the template, we used the ligand from 3MAX PDB entry [2], Figure 1. (HDAC-2 isozyme has the identical active site with HDAC-1). The ChemBank set of 2346 molecules was taken from the ligand.info [3]. After the filtering (exclusion of the metal containing compounds, and limiting of the number of HBA (10) and HBD (5)) we obtained 1990 molecules, which are submitted to OMEGA [4] to generate conformational assemblies of the molecules studied. The OMEGA options were set to default, yielding ~ 142000 conformers in total. We searched the shape and the pharmacophoric similarity of the multiconformer ligand set against the template molecule by ROCS program [5]. The best-ranked solution of the 100 hits by TanimotoCombo score (1.305) was Nifenazone, that has been used as the analgesic drug and was withdrawn due to heavy side effects. The subset of ligand conformers prepared with ROCS is further submitted to EON [6], to search for the electrostatic similarity to the template molecule. The compound labeled as the itdac-7 in ChemBank appears as the best-ranked solution by the ET-combo score (1.403), Figure 1b. There is no literature data on this compound, but ChemBank results from the high-throughput screening campaigns indicates itdac-7 as active toward enzymes involved in deacetylation. Our preliminary screen, as reported in this communication, involves the MMFF94s charges ascribed by default. Further work will be directed to assignation of the semiempirical charges for the electrostatic similarity screen, using the larger database of the compounds. All calculations by OpenEye applications were performed in BJD work group on PARADOX cluster, Institute of Physics, Belgrade.
Acknowledgement: The work reported makes use of results produced by the High-Performance Computing Infrastructure for South East Europe’s Research Communities (HP-SEE), a project co-funded by the European Commission (under Contract Number 261499) through the Seventh Framework Programme HP-SEE (http://www.hp-see.eu/).
The Ministry of Education and Science of Serbia support this work. Grant 172035.
References: [1] Nature 389 (1997) 349; [2] Bioorg. Med. Chem. Lett. 20 (2010) 3142; [3] Comb. Chem. High. Throughput Screen. 7 (2004) 757; [4] J. Chem. Inf. Model. 50 (2010) 572, OMEGA 2.4.2; [5] J. Med. Chem. 48 (2005) 1489, ROCS 3.1.1; [6] EON 2.0.1, OpenEye Scientific Software, Inc., Santa Fe, NM, USA, www.eyesopen.com .
Primary author
Mr
Cvijetić Ilija N.
(Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski Trg 12-16, Belgrade)
Co-authors
Prof.
Alessandro Pedretti
(Department of Pharmaceutical Sciences, Drug Design Laboratory, University of Milan, Italy)
Branko Drakulic
(Department of Chemistry-IChTM, University of Belgrade)
Prof.
Giulio Vistoli
(Department of Pharmaceutical Sciences, Drug Design Laboratory, University of Milan, Italy)
Prof.
Ivan O. Juranić
(Department of Chemistry-IChTM, University of Belgrade, Njegoševa 12, Belgrade, Serbia)
