Trends in Pharmaceutical Sciences and Technologies

Trends in Pharmaceutical Sciences and Technologies

Cross Docking Study Directed Toward Virtual Screening and Molecular Docking Study of Phenanthrene 1,2,4-triazine Derivatives As Novel Bcl-2 Inhibitors

Document Type : Research(Original) Article

Authors
Mohammad Hasan Jamei
Mehdi khoshneviszadeh
Najmeh Edraki
Maryam Firoozi
Zahra Haghighijoo
Rmin Miri
Amirhossein sakhtaman
Abstract
Apoptosis is critical for tissue homeostasis and for the physiological removal of abnormal cells. Bcl-2 family proteins are important regulators of apoptosis. It’s observed that antiapototic Bcl-2 family members are generally over expressed in many cancer cells. As a result, it has stimulated a growing interest in the discovery of small molecules targeting such proteins as potential anticancer therapeutics. With the aim of designing and virtual screening of new phenanthrene based Bcl-2 inhibitors, we performed a cross-docking study. This study is done for different available Bcl-2 X-ray crystal structures in order to find the most appropriate PDB code of this enzyme. After analytical analyses, we found a PDB code for the enzyme. Designed library of phenanthrene triazine containing different hydrazone moieties was further screened using selected crystal structure. It identifies the ligand which interacts the target with lower binding energy. As a conclusion, cross docking study could be a validated strategy for finding the most appropriate crystal structure for docking study. Our designed library of phenanthrene triazine-based derivatives containing hydrazone pendant could be served as potential candidates for Bcl-2 inhibition.
Keywords
apoptosis
Bcl-2
Cross docking
Virtual screening
Phenanthrene triazine
  1. Al-Karaawi MA. Interaction studies to evaluate 2-carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl. chemotherapy. 2013;7(8):9.
  2. Goodsell DS, Olson AJ. Automated docking of substrates to proteins by simulated annealing. Proteins: Structure, Function, and Bioinformatics. 1990;8(3):195-202.
  3. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry. 2009;30(16):2785-91.
  4. Vogler M. Targeting BCL2-proteins for the treatment of solid tumours. Advances in medicine. 2014;2014.
  5. Sudhakar A. History of cancer, ancient and modern treatment methods. Journal of cancer science & therapy. 2009;1(2):1-2.
  6. Camperchioli A, Mariani M, Bartollino S, Petrella L, Persico M, Orteca N, et al. Investigation of the Bcl-2 multimerisation process: Structural and functional implications. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2011;1813(5):850-7.
  7. Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. Journal of cell science. 2009;122(16):2801-8.
  8. Tzifi F, Economopoulou C, Gourgiotis D, Ardavanis A, Papageorgiou S, Scorilas A. The role of BCL2 family of apoptosis regulator proteins in acute and chronic leukemias. Advances in hematology. 2011;2012.
  9. Mohammadi MK, Firuzi O, Khoshneviszadeh M, Razzaghi-Asl N, Sepehri S, Miri R. Novel 9-(alkylthio)-Acenaphtho [1, 2-e]-1, 2, 4-triazine derivatives: synthesis, cytotoxic activity and molecular docking studies on B-cell lymphoma 2 (Bcl-2). DARU Journal of Pharmaceutical Sciences. 2014;22(1):1.
  10. Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, et al. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. Journal of medicinal chemistry. 2001;44(25):4313-24.
  11. Wang J-L, Liu D, Zhang Z-J, Shan S, Han X, Srinivasula SM, et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proceedings of the National Academy of Sciences. 2000;97(13):7124-9.
  12. Chen CY-C. Computational screening and design of traditional Chinese medicine (TCM) to block phosphodiesterase-5. Journal of Molecular Graphics and Modelling. 2009;28(3):261-9.
  13. Bissantz C, Folkers G, Rognan D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. Journal of medicinal chemistry. 2000;43(25):4759-67.
  14. Davood A, Iman M, Nematollahi A, Shafiee A. Docking and QSAR studies of new 1, 4-dihydropyridines containing 4 (5)-chloro-2-methyl-5 (4)-imidazolyl substituent. Medicinal Chemistry Research. 2012;21(3):325-32.
  15. Gohlke H, Klebe G. Statistical potentials and scoring functions applied to protein–ligand binding. Current opinion in structural biology. 2001;11(2):231-5.
  16. Schneider G, Böhm H-J. Virtual screening and fast automated docking methods. Drug discovery today. 2002;7(1):64-70.
  17. Razzaghi-Asl N, Ebadi A, Edraki N, Mehdipour A, Shahabipour S, Miri R. Response surface methodology in docking study of small molecule BACE-1 inhibitors. Journal of molecular modeling. 2012;18(10):4567-76.
Trends in Pharmaceutical Sciences and Technologies
Volume 2, Issue 4 - Serial Number 4
10
December 2016
Pages 253-258