Mô phỏng động học phân tử và nghiên cứu tràn phân tử của vùng liên kết ligands của thụ thể retinoid X

Journal of Molecular Modeling - Tập 23 - Trang 1-9 - 2017
Geoffrey M. Gray1, Ning Ma1, Carl E. Wagner2, Arjan van der Vaart1
1Department of Chemistry, University of South Florida, Tampa, USA
2School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts & Sciences, Arizona State University, Glendale, USA

Tóm tắt

Bexarotene là một chất đồng vận thụ thể retinoid X (RXR) được FDA chấp thuận để điều trị ung thư tế bào T cutaneous, và việc sử dụng nó trong các loại ung thư khác và bệnh Alzheimer đang được nghiên cứu. Thuốc này gây ra những tác dụng phụ nghiêm trọng, có thể được giảm thiểu qua các sửa đổi hóa học của phân tử. Để hợp lý hóa các chất đồng vận đã biết và giúp xác định các vị trí cho các thay thế tiềm năng, chúng tôi trình bày các mô phỏng phân tử trong đó vùng liên kết ligand RXR được tràn ngập với một số lượng lớn các phân tử giống thuốc, cùng với các mô phỏng động học phân tử của một loạt các ligand giống bexarotene gắn vào vùng liên kết ligand RXR. Dựa trên các mô phỏng tràn ngập, hai vùng quan tâm cho các sửa đổi ligand đã được xác định: một vùng kị nước gần vị trí cầu nối và một vùng khác gần vòng hợp nhất. Ngoài ra, sự dao động vị trí của vòng phenyl thường nhỏ hơn so với dao động của vòng hợp nhất của các ligand. Các quan sát này cho thấy rằng vòng hợp nhất có thể là một mục tiêu tốt để thiết kế các ligand giống bexarotene có độ affin cao hơn, trong khi vòng phenyl đã được tối ưu hóa. Thêm vào đó, đã quan sát thấy những khác biệt đáng kể trong vị trí ligand và tương tác giữa RXRα và RXRβ, cũng như sự khác biệt trong liên kết hydro và sự hòa tan, điều này có thể được khai thác trong sự phát triển của các ligand đặc hiệu cho từng phân loài.

Từ khóa

#Bexarotene #thụ thể retinoid X #mô phỏng động học phân tử #ligand #ung thư #bệnh Alzheimer

Tài liệu tham khảo

Dawson MI, Xia ZB (2012) The retinoid X receptors and their ligands. Biochim Biophys Acta Mol Cell Biol Lipids 1821:21–56 Lefebvre P, Benomar Y, Staels B (2010) Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab 21:676–683 Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, de Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58:760–772 Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM (1992) Characterization of 3 RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6:329–344 Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C (1992) 9-Cis retinoic acid is a high-affinity ligand for the retinoid-X receptor. Cell 68:397–406 Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, Grippo JF (1992) 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR-α. Nature 355:359–361 Wolf G (2006) Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev 64:532–538 Calleja C, Messaddeq N, Chapellier B, Yang HY, Krezel W, Li M, Metzger D, Mascrez B, Ohta K, Kagechika H, Endo Y, Mark M, Ghyselinck NB, Chambon P (2006) Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes. Genes Dev 20:1525–1538 Radominska-Pandya A, Chen GP (2002) Photoaffinity labeling of human retinoid X receptor beta (RXR beta) with 9-cis-retinoic acid: Identification of phytanic acid, docosahexaenoic acid, and lithocholic acid as ligands for RXR beta. Biochemistry 41:4883–4890 Lengqvist J, de Urquiza AM, Bergman AC, Willson TM, Sjovall J, Perlmann T, Griffiths WJ (2004) Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor alpha ligand-binding domain. Mol Cell Proteomics 3:692–703 Ziouzenkova O, Orasanu G, Sukhova G, Lau E, Berger JP, Tang GW, Krinsky NI, Dolnikowski GG, Plutzky J (2007) Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses. Mol Endocrinol 21:77–88 Brelivet Y, Rochel N, Moras D (2012) Structural analysis of nuclear receptors: from isolated domains to integral proteins. Mol Cell Endocrinol 348:466–473 Germain P, Iyer J, Zechel C, Gronemeyer H (2002) Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415:187–192 Perez E, Bourguet W, Gronemeyer H, de Lera AR (2012) Modulation of RXR function through ligand design. Biochim Biophys Acta Mol Cell Biol Lipids 1821:57–69 Glass CK, Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14:121–141 Kassam A, Miao B, Young PR, Mukherjee R (2003) Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding. J Biol Chem 278:10028–10032 McNamara P, Seo SB, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA (2001) Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105:877–889 Tang XW (2010) Bexarotene: a promising anticancer agent. Cancer Chemoth Pharm 65:201–205 Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA (1994) Synthesis and structure-activity-relationships of novel retinoid-X receptor-selective retinoids. J Med Chem 37:2930–2941 Burg G, Dummer R (2000) Historical perspective on the use of retinoids in cutaneous T-cell lymphoma (CTCL). Clin Lymphoma 1:S41–S44 Zhang CL, Hazarika P, Ni X, Weidner DA, Duvic M (2002) Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: Relevance to mechanism of therapeutic action. Clin Cancer Res 8:1234–1240 Yen WC, Prudente RY, Corpuz MR, Negro-Vilar A, Lamph WW (2006) A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. Br J Cancer 94:654–660 Cramer PE, Cirrito JR, Wesson DW, Lee CYD, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506 Fitz NF, Cronican AA, Lefterov I, Koldamova R (2013) Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924–924 Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, Jucker M, Holtzman DM, Tanzi RE, Vassar R, Sisodia SS (2013) Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924–924 Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, Gijsen H, Moechars D, Mercken M, Kemp J, D’Hooge R, De Strooper B (2013) Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924–924 Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM (2013) Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924–924 Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW, Brunden KR, Wilson DA (2013) Response to Comments on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924–924 Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, Duvic M (1999) Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 340:1075–1079 Galper SL, Smith BD, Wilson LD (2010) Diagnosis and management of mycosis fungoides. Oncology 24:491–501 Sokolowska-Wojdylo M, Lugowska-Umer H, Maciejewska-Radomske A (2013) Oral retinoids and rexinoids in cutaneous T-cell lymphomas. Adv Dermatol Allergol 30:19–29 Wagner CE, Jurutka PW, Marshall PA, Groy TL, van der Vaart A, Ziller JW, Furmick JK, Graeber ME, Matro E, Miguel BV, Tran IT, Kwon J, Tedeschi JN, Moosavi S, Danishyar A, Philp JS, Khamees RO, Jackson JN, Grupe DK, Badshah SL, Hart JW (2009) Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). J Med Chem 52:5950–5966 Furmick JK, Kaneko I, Walsh AN, Yang JN, Bhogal JS, Gray GM, Baso JC, Browder DO, Prentice JLS, Montano LA, Huynh CC, Marcus LM, Tsosie DG, Kwon JS, Quezada A, Reyes NM, Lemming B, Saini P, van der Vaart A, Groy TL, Marshall PA, Jurutka PW, Wagner CE (2012) Modeling, synthesis and biological evaluation of potential retinoid X receptor-selective agonists: novel halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). ChemMedChem 7:1551–1566 Raman EP, Yu W, Guvench O, Mackerell AD (2011) Reproducing crystal binding modes of ligand functional groups using site-identification by ligand competitive saturation (SILCS) simulations. J Chem Inf Model 51:877–896 Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38 Egea PF, Mitschler A, Moras D (2002) Molecular recognition of agonist ligands by RXRs. Mol Endocrinol 16:987–997 Love JD, Gooch JT, Benko S, Li C, Nagy L, Chatterjee VK, Evans RM, Schwabe JW (2002) The structural basis for the specificity of retinoid-X receptor-selective agonists: new insights into the role of helix H12. J Biol Chem 277:11385–11391 Brooks BR, Brooks CL III, MacKerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) CHARMM: The biomolecular simulation program. J Comput Chem 30:1545–1614 Best RB, Zhu X, Shim J, Lopes PEM, Mittal J, Feig M, MacKerell AD (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone phi, psi and side-chain chi(1) and chi(2) dihedral angles. J Chem Theory Comput 8:3257–3273 Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671–690 Anandakrishnan R, Aguilar B, Onufriev AV (2012) H++3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Res 40:W537–W541 Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J Comput Phys 23:327–341 Martyna GJ, Klein ML, Tuckerman M (1992) Nose-Hoover chains - the canonical ensemble via continuous dynamics. J Chem Phys 97:2635–2643 Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092 Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791 O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open Babel: an open chemical toolbox. J Cheminform 3:33 Santin EP, Germain P, Quillard F, Khanwalkar H, Rodriguez-Barrios F, Gronemeyer H, Lera AR, Bourguet W (2009) Modulating retinoid X receptor with a series of (E)-3- 4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapht halen-2-yl)phenyl acrylic acids and their 4-alkoxy isomers. J Med Chem 52:3150–3158 Conda-Sheridan M, Park EJ, Beck DE, Reddy PVN, Nguyen TX, Hu BJ, Chen L, White JJ, van Breemen RB, Pezzuto JM, Cushman M (2013) Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential. J Med Chem 56:2581–2605 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 46:3–26 Shen J, Cheng FX, Xu Y, Li WH, Tang Y (2010) Estimation of ADME properties with substructure pattern recognition. J Chem Inf Model 50:1034–1041 Daina A, Michielin O, Zoete V (2014) iLOGP: A simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model 54:3284–3301