High-throughput Screening of New Antimitotic Compounds Based on Potential of Virtual Organization CSLabGrid
DOI:
https://doi.org/10.15407/scin11.01.092Keywords:
Grid, virtual organization, structural bioinformatics, cytoskeleton, tubulin, benzimidazole compounds, tubulin depolymerization, antimitotic activity, molecular docking, high-throughput screening, drugs.Abstract
In the frameworks of virtual organization CSLabGrid using Grid calculations the repository of 3-D models of cytoskeletal proteins (tubulins and FtsZ-proteins) verified by stereochemistry, is described. The repository of structures of canonical antimicrotubular compounds (inhibitors of tubulin polymerization) as well as library of ligands, suitable for high-throughput screening (HTS) in Grid were created. According to the results of the library HTS 1,164 compounds that demonstrated an elevated affinity to tubulin molecules: 205 — to α-tubulin and 959 — to β-tubulin were selected. It was found that among 2,886 compounds synthesized in the Institute of Organic Chemistry of NAS of Ukraine, 6 were perspective inhibitors of α- and β-tubulin polymerization in such human pathogens as Pneumocystis carinii, Giardia intestinalis Ajellomyces capsulatus, Neosartorya fumigata and Candida albicans. Respectively, these compounds were recommended for subsequent experimental evaluation of their biological activity for use as new pharmacological agents.
References
Vignaud, T., Blanchoin, L., and Théry, M.: Directed Cytoskeleton Self-Organization. Trends Cell Biol., 22, 12, 671–682 (2012).
https://doi.org/10.1016/j.tcb.2012.08.012
Eren, E.C., Gautam, N., and Dixit, R.: Computer Simulation and Mathematical Models of the Noncentrosomal Plant Cortical Microtubule Cytoskeleton. Cytoskeleton, 69, 3, 144–154 (2012).
https://doi.org/10.1002/cm.21009
Massarotti, A., Theeramunkong, S., Mesenzani, O. et al. Identification of Novel Antitubulin Agents by Using a Virtual Screening Approach Based on a 7-Point Pharmacophore Model of the Tubulin Colchi-Site. Chem. Biol. Drug Des., 78, 6, 913–922 (2011).
https://doi.org/10.1111/j.1747-0285.2011.01245.x
Sui, M., Zhang, H., Di, X. et al.: G2 Checkpoint Abrogator Abates the Antagonistic Interaction between Antimic rotubule Drugs and Radiation Therapy. Radiother. Oncol., 104, 2, 243–248 (2012).
https://doi.org/10.1016/j.radonc.2012.04.021
Henriquez, F.L., Ingram, P.R., Muench, S.P. et al.: Molecular Basis for Resistance of Acanthamoeba Tubulins to All Major Classes of Antitubulin Compounds. Antimicrob Agents Chemother, 52, 3, 1133–1135 (2008).
https://doi.org/10.1128/AAC.00355-07
Zhao, Y., Wu, F., Wang, Y. et al.: Inhibitory Action of Chamaejasmin A against Human HEP-2 Epithelial Cells: Effect on Tubulin Protein. Mol Biol Rep., 39, 12, 11105–11112 (2012).
https://doi.org/10.1007/s11033-012-2016-y
Pilhofer, M. and Jensen, G.J.: The Bacterial Cytoskeleton: More than Twisted Filaments. Curr Opin Cell Biol., 25, 125–133 (2013).
https://doi.org/10.1016/j.ceb.2012.10.019
Haglund, C.M. and Welch, M.D.: Pathogens and Polymers: Microbe-Host Interactions Illuminate the Cytoskeleton. J. Cell Biol., 195, 1, 7–17 (2011).
https://doi.org/10.1083/jcb.201103148
Tuszynski, J.A., Craddock, T.J., Mane, J.Y. et al.: Modeling the Yew Tree Tubulin and a Comparison of Its Interaction with Paclitaxel to Human Tubulin. Pharm Res., 29, 11, 3007–3021 (2012).
https://doi.org/10.1007/s11095-012-0829-y
Calvo, E., Barasoain, I., Matesanz, R. et al.: Cyclostreptin Derivatives Specifically Target Cellular Tubulin and Further Map the Paclitaxel Site. Biochemistry, 51, 1, 329–341 (2012).
https://doi.org/10.1021/bi201380p
Sörensen, P.M., Iacob, R.E., Fritzsche, M. et al.: The Natural Product Cucurbitacin E Inhibits Depolymerization of Actin Filaments. ACS Chem Biol., 7, 9, 1502–1508 (2012).
https://doi.org/10.1021/cb300254s
Desouza, M., Gunning, P.W., and Stehn, J.R.: The Actin Cytoskeleton as a Sensor and Mediator of Apoptosis. Bioarchitecture, 2, 3, 75–87 (2012).
https://doi.org/10.4161/bioa.20975
Anderson-White, B., Beck, J.R., Chen, C.T. et al.: Cytoskeleton Assembly in Toxoplasma Gondii Cell Division. Int Rev Cell Mol Biol., 298, 1–31 (2012).
https://doi.org/10.1016/B978-0-12-394309-5.00001-8
Pei, W., Du, F., Zhang, Y., He, T., and Ren, H.: Control of the Actin Cytoskeleton in Root Hair Development. Plant Sci., 187, 10–18 (2012).
https://doi.org/10.1016/j.plantsci.2012.01.008
Demchuk, O., Karpov, P., and Blume, Ya.: Docking Small Ligands to Molecule of the Plant FtsZ Protein: Application of the CUDA Technology for Faster Computations. Cytol. Genetics, 46, 3, 172–179 (2012).
https://doi.org/10.3103/S0095452712030048
Pydiura, N., Karpov, P., and Blume, Ya.: Hybrid CPU-GPU Calculations – a Promising Future for Computational Biology. Third Int. Conference «High Performance Computing» HPC-UA 2013, 330–335 (2013).
Pydiura, N., Karpov, P., and Blume, Ya.: Hardware Environment for CSLabGrid: Reaching Maximum Efficacy of Computations in Structural Biology and Bioinformatics. Second Int. Conference «Cluster Computing» CC 2013, 191–194 (2013).
Pydiura, N., Karpov, P., and Blume, Ya.: On the Efficiency of CPU and Hybrid CPU-GPU Systems in Computational Biology Tasks. Comput. Sci. Applicat., 1, 1, 48–59 (2014).
Pydiura, N., Karpov, P., and Blume, Ya.: Design of Specific Cytoskeleton Related Biological Database and Data Management Environment for Bioinformatical Cytoskeleton Investigation and Collaboration within Virtual Grid-Organisation. Proc. of the Int. Moscow Conference on Comput. Mol. Biol., 297–298 (2011).
Roy, A., Kucukural, A., and Zhang, Y.: I-TASSER: a Unified Platform for Automated Protein Structure and Function Prediction. Nature Protocols, 5, 725–738 (2010).
https://doi.org/10.1038/nprot.2010.5
Webb, B. and Sali, A.: Comparative Protein Structure Mo deling Using MODELLER. Curr Protoc Bioinformatics, 47, 5.6.1 – 5.6.32 (2014).
https://doi.org/10.1002/0471250953.bi0506s47
Tsai, K.C., Wang, S.H., Hsiao, N.W. et al.: The Effect of Different Electrostatic Potentials on Docking Accuracy: a Case Study Using DOCK5.4. Bioorg Med Chem Lett., 18, 12, 3509–3512 (2008).
https://doi.org/10.1016/j.bmcl.2008.05.026
Ouyang, X., Chen, X., Piatnitski, E.L. et al.: Synthesis and Structure-Activity Relationships of 1,2,4-Triazoles as a Novel Class of Potent Tubulin Polymerization Inhibitors. Bioorg. Med. Chem. Lett., 15, 5154–5159 (2005).
