Speaker
Branko Drakulic
(Department of Chemistry-IChTM, University of Belgrade)
Description
The 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids (Scheme 1) exert antiproliferative potency and significant selectivity toward human tumor cells in vitro in low micromolar to submicromolar concentrations [1]. In the congeneric set of compounds we observed the regularity between the selectivity and the properties derived from the conformational assemblies of compounds [2]. As the part of ongoing studies, in this communication we repot the free-energy surfaces of the representative congeners (some examples is given on the Figure 1), as obtained by molecular dynamics simulations, using adaptive biasing force (ABF) procedure [3] to speed-up sampling of the systems. All simulations were performed involving simulation of explicit solvents having different polarity and hydrogen bond donor/acceptor abilities (water, chloroform, dimethyl-sulfoxide, ethanol, n-octanol/water mixture), lasting from 20 to 50 ns. For comparison, the molecular dynamics simulations on the representative system without applied biasing forces was also reported. The differences in the free-energy surfaces of the same, representative, congener in different solvents reflect the fact that flexible molecules change conformations in a way to mimic surroundings (i.e. solvent in which are dissolved) [4]. Ranges of property spaces [5] of compounds under the study were analyzed and compared. In all simulations molecules were treated in their neutral form. The 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 simulation, 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 treated by Particle Mesh Ewald method. The periodic boundary conditions were applied, and 12 Å cut-off (8 Å switching), with pair list distances set to 13.5 Å. All calculations were performed by NAMD 2.8 [6] on the multimode Linux cluster. For the preparation of the systems and analysis of the results VegaZZ 2.4.0 was used [7].
Acknowledgement: The work is supported 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.
References: [1] J. Med. Chem. 48 (2005) 5600; [2] a) The 18th European Symposium on Quantitative Structure-Activity Relationships, Book of Abstracts, pp. 278-279, Greece, 2010; b) The 19th European Symposium on Quantitative Structure-Activity Relationships, Book of Abstracts, p 147, Austria, 2012; [3] J. Chem. Theory Comput. 6 (2010) 35; [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
Primary author
Branko Drakulic
(Department of Chemistry-IChTM, University of Belgrade)
Co-author
Prof.
Ivan O. Juranić
(Department of Chemistry-IChTM, University of Belgrade, Njegoševa 12, Belgrade, Serbia)
