Selection the Drug Efficacy of Oroidin Derivatives as Hsp90 Inhibitors by Computer Aided Drug Design Method
Abstract
Heat shock protein 90 (Hsp90) is a conserved molecular chaperone associated with regulation of hundreds of client proteins that are key drivers, regulators and promoters of numerous refractory diseases including cancer. Consequently, Hsp90 is a significant target for the development of harmless anticancer therapies. Marine organisms are the rich source of pharmacological important compounds, especially oroidin. Oroidin, a pyrrole-2-aminoimidazole alkaloid, isolated from the marine sponge Agelas oroides, binds ATP pocket of Hsp90 and suppresses the ATPase activity of the protein. Natural product oroidin was selected as potent inhibitor of Hsp90 and its drug candidature was accordingly improved by substituting various functional groups. Virtual screenings were done through in silico studies, carried out on thirty nine derivatives of oroidin. DFT study was performed with Gaussian16, UB3LYP/6-311G++ (d, p) basis set to investigate the quantum mechanical parameters such as HOMO-LUMO energies, dipole moments. Derived parameters like ionization potential, electron affinity, softness-hardness, chemical potential and electrophilicity index were also calculated. Using AutoDock 4.0 programme, we studied docking of the thirty-nine designed derivatives with macromolecule Hsp90 and recorded the binding energy values of the best conformation out of nine in each docked compound. ADME predictions, molecular descriptor properties, and theoretical toxicity tests were evaluated using preADMET, molinspiration, and OSIRIS property explorer web tools respectively. We found twenty eight derived compounds, each docked at the same region of Hsp90, possessing higher binding energies compare to the precursor oroidin. Seven of them qualified all the rules of drug candidature and could be safe in using as effective drugs for cancer treatment. This study suggests that these compounds could be synthesized for in vitro test and may leads to a novel anticancer therapeutics.
Keywords:
Hsp90, inhibitor, Oroidin, Molecular docking, DFT, ADME prediction, Molecular descriptor properties.DOI
https://doi.org/10.25004/IJPSDR.2020.120607References
World Health Organization. Health Topics: Cancer. ehttps://www.who.int/news-room/fact-sheets/detail/cancr (Accessed July 06, 2020)
Abd El-Hack ME, Abdelnour S, Alagawany M, Abdo M, Sakr MA, Khafaga AF, Mahgoub SA, Elnesr SS, Gebriel MG. Microalgae in modern cancer therapy: current knowledge. Biomed. Pharmacother. 2019; 111:42-50.
Jhaveri K, Taldone, Modi S, Chiosis G. Advances in the clinical development of heat shock protein 90 (hsp90) inhibitors in cancers. Biochim. Biophys. Acta. 2012; 1823(3):742-755.
Vabulas RM, Raychaudhuri S, Hartl HM, Hartl FU. Protein folding in the cytoplasm and the heat shock response. Cold Spring Harb Perspect. Biol. 2010; 2(12):a004390.
Gupta SC, Sharma A, Mishra M, Mishra RK, Chowdhuri DK. Heat shock proteins in toxicology: how close and how far?. Life Sci. 2010; 86(11-12):377-384.
Lee HJ, Ock CY, Kim SJ, Hahm KB. Heat shock protein: hard worker or bad offender for gastric diseases. Int. J. Proteomics. 2010; 2010:259163.
Chen B, Zhong D, Monteiro A. Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms. BMC Genomics. 2006; 7:156.
Chen B, Piel WH, Gui L, Bruford E, Monteiro A.The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics. 2005; 86(6):627-637.
Goetz MP, Toft DO, Ames MM, Erlichman C. The Hsp90 chaperone complex as a novel target for cancer therapy. Ann. Oncol. 2003; 14 (8):1169–1176.
Taipale M, Jarosz DF, Lindquist S. Hsp90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell. Bio. 2010; 11(7):515-528.
Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic hsp90 complex in cancer. Nat. Rev. Cancer. 2010; 10(8):537-549.
Lillsunde KE, Tomašič T, Kikelj D, Tammela P. Marine alkaloid oroidin analogues with antiviral potential: A novel class of synthetic compounds targeting the cellular chaperone Hsp90. Chem Biol Drug Des. 2017; 90(6):1147-1154.
Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB. Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res. 2008; 68 (2):589–596.
Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP, Wang CX, Hilsenbeck SG, Osborne CK, Allred DC, Elledge R, Chang JC. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J. Clin. Oncol. 2005; 23(11):2460–2468.
Duerfeldt AS, Blagg BSJ. Hsp90 inhibition: elimination of shock and stress. Bioorg. Med. Chem. Lett. 2010; 20(17):4983-4987.
Prodromou C, Nuttall JM, Millson SH, Roe SM, Sim TS, Tan D, Workman P, Pearl LH, Piper PW. Structural basis of the radicicol resistance displayed by afungal hsp90. Acs. Chem. Biol, 2009; 4(4):289-297.
Chiosis G, Lopes CE, Solit D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr. Opin. Investig. Drugs. 2006; 7 (6):534–541.
Lees-Miller SP, Anderson CW. The human double-stranded dna-activated proteinkinase phosphorylates the 90-kda heat-shock protein, hsp90 alpha at two nh2-terminal threonine residues. J. Biol. Chem. 1989; 264:17275-17280.
Kurokawa M, Zhao C, Reya T, Kornbluth S. Inhibition of apoptosome formation bysuppression of hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Mol. Cell. Biol. 2008; 28:5494-5506.
Rong B, Yang S, Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review). Int. J. Oncol. 2018; 52(2):321-336.
Pires ES, Khole VV. A block in the road to fertility: autoantibodies to heat-shock protein 90-beta in human ovarian autoimmunity. Fertil. Steril. 2009; 92 (4):1395-1409.
Donnelly A, Blagg BSJ. Novobiocin and additional inhibitors of the hsp90 c-terminal nucleotide-binding pocket. Curr. Med. Chem. 2008; 15:2702-2717.
Mehbub MF, Lei J, Franco C, Zhang W. Marine sponge derived natural products between 2001 and 2010: trends and opportunities for discovery of bioactives. Mar. Drugs. 2014; 12(8):4539-4577.
Molinski TF, Dalisay DS, Lievens SL, Saludes JP. Drug development from marine natural products. Nat. Rev. Drug. Discov. 2009; 8(1):69-85.
Rentas AL, Rosa R, Rodríguez AD, De Motta GE. Effect of alkaloid toxins from tropical marine sponges on membrane sodium currents. Toxicon. 1995; 33(4):491-497.
Al-Mourabit A, Potier P. Sponge's molecular diversity through the ambivalent reactivity of 2-aminoimidazole: a universal chemical pathway to the oroidin-based pyrrole-imidazole alkaloids and their palau'amine congeners. Eur. J. Org. Chem. 2001; 2:237-243.
Hoffmann H, Lindel T. Synthesis of the pyrrole-imidazole alkaloids. Synthesis. 2003; 12:1753-1783.
Al-Mourabit A, Zancanella MA, Tilvi S, Romo D. Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids. Nat. Prod. Rep. 2011; 28(7):1229-1260.
Davis RA, Fechner GA, Sykes M, Garavelas A, Pass DM, Carroll AR, Addepalli R, Avery VM, Hooper JNA, Quinn RJ. Dibromophakellin: an alpha2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata. Bioorg. Med. Chem. 2009; 17:2497-2500.
Henry SH, Bosch FX, Bowers JC. Aflatoxin, hepatitis and worldwide liver cancer risks. Adv. Exp. Med. Biol. 2002; 504:229-233.
Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006; 368(9550):1894-1907.
Tomašić T, Nabergoj D, Vrbek S, Zidar N, Jakopin Ž, Žula A, Hodnik Ž, Jukič M, Anderluh M, Ilaš J, Dolenc MS, Peluso J, Ubeaud-Séquier G, Muller CD, Mašič LP, Kikelj D. Analogues of the marine alkaloids oroidin, clathrodin, and hymenidin induce apoptosis in human HepG2 and THP-1 cancer cells. Med. Chem. Commun. 2015; 6:105–110.
Dyson L, Wright AD, Young KA, Sakoff JA, McCluskey A. Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin. Bioorg. Med. Chem. 2014; 22(5):1690-1699.
Kadam RU, Roy N. Recent trends in Drug-Likeliness Prediction: A comprehensive review of In Silico methods. Indian J. Pharm. Sci. 2009; 14:609-615.
Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr. Opin. Chem. Biol. 2002; 6:439-446.
Molegro Molecular Viewer (MMV) 2.5.0. CLC Bio, Qiagen Inc, software available at http://www.clcbio.com/products/ clc-drug-discovery-workbench.2012.
ACD/Structure Elucidator version 2018.1. Advanced Chemistry Development Inc. Toronto, ON, Canada, www.acdlabs.com. 2019.
Dreizler RM, da J. Providencia Density Functional Methods in Physics. Plenum Press, New York, 1985.
Parr RG, Yang W. Density-Functional Theory of Atoms and Molecules. Oxford University Press, New York, 1989.
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA, Jr Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin K.N, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian, Inc. Wallingford CT, Gaussian 16, Revision C.01. 2016.
Stephens P, Devlin F, Chabalowski C, Frisch MJ. Ab initio calculation of vibrational absorptionand circular dichroism spectra using density functional force fields. J. Phys. Chem. 1994; 98:11623-11627.
Lee C, Yang W, Parr RG. Development of the Colle-Salvetti correlation-energy formula into afunctional of the electron density. Phys. Rev. B Condens. Matter. 1988; 37(2):785-789.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J. Computational Chemistry. 2009; 16: 2785-2791.
Sanner MF. Python: A Programming Language for Software Integration and Development. J. Mol. Graph Mod. 1999; 17 (1):57-61.
Rastogi SC, Mmendiratta N, Rastogi P. Bioinformatics Methods and Applications Genomics, proteomics and Drug Discovery: Structural Biology and Virtual screening for Drug Discovery. 4th ed, PHL Learning Private Limited, Delhi, 2015, pp. 426-444.
Fleming I. Frontier Orbital and Organic Chemical Reactions. John Wiley and Sons, New York, 1976.
Reed, J.L. Electronegativity: Chemical hardness I. J. Phys. Chem. A. 1997; 101 (40):7396-7400.
Barim E, Akman F. Synthesis. characterization and spectroscopic investigation of N-(2- acetylbenzofuran-3-yl) acrylamide monomer: Molecular structure, HOMO-LUMO study, TD-DFT and MEP analysis. Journal of Molecular Structure. 2019; 1195:506-513.
Pauling L. The nature of the chemical bond and the structure of molecules and crystals: an introduction to modern structural chemistry. Cornell university press, 1960.
Parr RG, Yang W. Density functional approach to the frontier-electron theory of chemical reactivity. J. Am. Chem. Soc. 1984; 106:4049-4050.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliver Rev. 2001; 23:4–25.
Husain A, Ahmad A, Khan SA, Asif M, Bhutani R, Al-Abbasi FA. Synthesis. molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents. Saudi Pharm. J. 2016; 24:104–114.
Tiwary BK, Pathak RK, Pradhan K, Nanda AK, Bothra AK, Chakraborty R. Evaluation of drug candidature of some quinazoline- 4-(3H)-ones as inhibitor of human dihydrofolatereductase enzyme: molecular docking and in silico studies. Int. J. Pharm. Pharm. Sci. 2014; 6:393-400.
Lee SK, Lee IH, Kim HJ, Chang GS, Chung JE, No KT. The PreADME Approach: web-based program for rapid prediction of physicochemical, drug absorption and drug-like properties, Euro QSAR 2002 designing drugs and crop protectants: processes, problems and solutions. Blackwell Publishing Maldenh, USA, 2003, pp. 418-420.
Ding F, Peng W. Biological activity of natural flavonoids as impacted by protein flexibility: An example of flavanones. Molecular Bio. Systems. 2015; 11 (4):1119-1133.
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