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SUMMARY:In the search of the HDAC-1 inhibitors. The preliminary results of
  ligand based virtual screening.
DTSTART;VALUE=DATE-TIME:20121019T120000Z
DTEND;VALUE=DATE-TIME:20121019T123000Z
DTSTAMP;VALUE=DATE-TIME:20261011T092025Z
UID:indico-contribution-160@indico.ipb.ac.rs
DESCRIPTION:Speakers: Cvijetić Ilija N. (Innovation Center of the Faculty
  of Chemistry\, University of Belgrade\, Studentski Trg 12-16\, Belgrade)\
 nAcetylation and deacetylation of histone is an important mechanism to reg
 ulate the DNA expression. Two main classes of enzymes catalyze this regula
 tory mechanism: histone acetyltransferase (HAT) and histone deacetylase (H
 DAC). HDACs are involved in signal transduction\, cell growth and cancer [
 1]. We report the results of the preliminary ligand-based virtual screenin
 g in the search of the novel HDAC-1 inhibitors. By this virtual screening 
 study\, we aimed to test the performances of the OpenEye applications inst
 alled on our home cluster PARADOX. As the template\, we used the ligand fr
 om 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 co
 mpounds\, and limiting of the number of HBA (10) and HBD (5)) we obtained 
 1990 molecules\, which are submitted to OMEGA [4] to generate conformation
 al assemblies of the molecules studied. The OMEGA options were set to defa
 ult\, yielding ~ 142000 conformers in total. We searched the shape and the
  pharmacophoric similarity of the multiconformer ligand set against the te
 mplate molecule by ROCS program [5]. The best-ranked solution of the 100 h
 its 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 the analgesic drug and was withdrawn due to heavy side effects.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 sol
 ution by the ET-combo score (1.403)\, Figure 1b. There is no literature da
 ta on this compound\, but ChemBank results from the high-throughput screen
 ing campaigns indicates itdac-7 as active toward enzymes involved in deace
 tylation. Our preliminary screen\, as reported in this communication\, inv
 olves the MMFF94s charges ascribed by default. Further work will be direct
 ed to assignation of the semiempirical charges for the electrostatic simil
 arity screen\, using the larger database of the compounds. All calculation
 s by OpenEye applications were performed in BJD work group on PARADOX clus
 ter\, Institute of Physics\, Belgrade.\nAcknowledgement: The work reported
  makes use of results produced by the High-Performance Computing Infrastru
 cture for South East Europe’s Research Communities (HP-SEE)\, a project 
 co-funded by the European Commission (under Contract Number 261499) throug
 h the Seventh Framework Programme HP-SEE (http://www.hp-see.eu/).\nThe Min
 istry of Education and Science of Serbia support this work. Grant 172035. 
 \nReferences: [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 (2
 005) 1489\, ROCS 3.1.1\; [6]  EON 2.0.1\, OpenEye Scientific Software\, In
 c.\, Santa Fe\, NM\, USA\, www.eyesopen.com .\n\nhttps://events.saifa.rs/e
 vent/291/contributions/160/
LOCATION:National Library of Serbia
URL:https://events.saifa.rs/event/291/contributions/160/
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