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SUMMARY:Free-energy surfaces of 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbu
 tanoic acids.  Molecular dynamics study in explicit solvents.
DTSTART;VALUE=DATE-TIME:20121019T110000Z
DTEND;VALUE=DATE-TIME:20121019T113000Z
DTSTAMP;VALUE=DATE-TIME:20261011T065400Z
UID:indico-contribution-191@indico.ipb.ac.rs
DESCRIPTION:Speakers: Branko Drakulic (Department of Chemistry-IChTM\, Uni
 versity of Belgrade)\nThe 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic
  acids (Scheme 1) exert antiproliferative potency and significant selectiv
 ity toward human tumor cells in vitro in low micromolar to submicromolar c
 oncentrations [1]. In the congeneric set of compounds we observed the regu
 larity between the selectivity and the properties derived from the conform
 ational assemblies of compounds [2]. As the part of ongoing studies\, in t
 his communication we repot the free-energy surfaces of the representative 
 congeners (some examples is given on the Figure 1)\, as obtained by molecu
 lar dynamics simulations\, using adaptive biasing force (ABF) procedure [3
 ] to speed-up sampling of the systems. All simulations were performed invo
 lving simulation of explicit solvents having different polarity and hydrog
 en bond donor/acceptor abilities (water\, chloroform\, dimethyl-sulfoxide\
 , ethanol\, n-octanol/water mixture)\, lasting from 20 to 50 ns. For compa
 rison\, the molecular dynamics simulations on the representative system wi
 thout applied biasing forces was also reported. The differences in the fre
 e-energy surfaces of the same\, representative\, congener in different sol
 vents reflect the fact that flexible molecules change conformations in a w
 ay to mimic surroundings  (i.e. solvent in which are dissolved) [4]. Range
 s of property spaces [5] of compounds under the study were analyzed and co
 mpared. In all simulations molecules were treated in their neutral form. T
 he effect of using different types of atomic charges on the final results 
 is also commented. All systems under the study were minimized during 20000
  steps\, than heated to 310 K for 10000 steps. Molecular dynamics simulati
 on\, on 310 ± 10 K\, with applied ABF procedure was performed on the each
  system. CHARMm22 force field and Geisteiger charges\, or charges derived 
 from the semiempirical calculations\, were used. Electrostatics was treate
 d by Particle Mesh Ewald method. The periodic boundary conditions were app
 lied\, and 12 Å cut-off (8 Å switching)\, with pair list distances set t
 o 13.5 Å. All calculations were performed by NAMD 2.8 [6] on the multimod
 e Linux cluster. For the preparation of the systems and analysis of the re
 sults VegaZZ 2.4.0 was used [7].\n\n\nAcknowledgement: The work is support
 ed by the European Commission under EU FP7 project HP-SEE\, http://www.hp-
 see.eu/. The Ministry of Education and Science of Serbia support this work
 . Grant 172035. \n\n\nReferences: [1] J. Med. Chem. 48 (2005) 5600\; [2] a
 ) The 18th European Symposium on Quantitative Structure-Activity Relations
 hips\, Book of Abstracts\, pp. 278-279\, Greece\, 2010\; b) The 19th Europ
 ean Symposium on Quantitative Structure-Activity Relationships\, Book of A
 bstracts\, p 147\, Austria\, 2012\; [3] J. Chem. Theory Comput. 6 (2010) 3
 5\; [4] Med. Res. Rev. 17 (1997) 303\; [5] J. Med. Chem. 48 (2005) 4947\; 
 [6] J. Compt. Chem. 26 (2005) 1781\; [7] J. Comp. Aided Mol. Des. 18 (2004
 ) 167\n\nhttps://events.saifa.rs/event/291/contributions/191/
LOCATION:National Library of Serbia
URL:https://events.saifa.rs/event/291/contributions/191/
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