Discovery of novel inhibitors of ghrelin O-acyltransferase enzyme: an in-silico approach

Faezeh Sadat Hosseini , Alireza Ghassempour, Massoud Amanlou

Abstract


Background and purpose: Ghrelin is known as a hunger hormone and plays a pivotal role in appetite, food intake, energy balance, glucose metabolism, and insulin secretion, making it a potential target for the treatment of obesity and type 2 diabetes. The essential maturation step of ghrelin to activate the GHS-R1a is the octanoylation of the Ser3, which is catalyzed by the ghrelin O-acyltransferase enzyme (GOAT) enzyme. Therefore, the inhibition of GOAT may be useful for treating ghrelin-related diseases.

Experimental approach: To discover the novel inhibitors against GOAT enzyme by a fast and accurate computational method, here, we tried to develop the homology model of GOAT. Subsequently, the generated model was stabilized by molecular dynamics simulation. The consecutive process of docking, pharmacophore mapping, and large-scale virtual screening were performed to find the potential hit compounds.

Findings / Results: The homology model of the GOAT enzyme was generated and the quality of 3D structures was increased to the highest level of > 99.8% of residue in allowed regions. The model was inserted into the lipid bilayer and was stabilized by molecular dynamics simulation in 200 ns. The sequential process of pharmacophore-based virtual screening led to the introduction of three compounds including ethaverine, kaempferitrin, and reglitazar as optimal candidates for GOAT inhibition.

Conclusion and implications: The results of this study may provide a starting point for further investigation for drug design in the case of GOAT inhibitors and help pave the way for clinical targeting of obesity and                   type 2 diabetes.


Keywords


Ghrelin O-acyltransferase enzyme; Molecular dynamics simulation; Obesity; Type 2 Diabetes; Virtual screening.

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References


Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9(3):381-388. DOI: 10.1038/nn1656.

Lim CT, Kola B, Korbonits M. The ghrelin/GOAT/GHS-R system and energy metabolism. Rev Endocr Metab Disord. 2011;12(3):173-186. DOI: 10.1007/s11154-011-9169-1.

Gahete MD, Córdoba-Chacón J, Kineman RD, Luque RM, Castaño JP. Role of ghrelin system in neuroprotection and cognitive functions: implications in Alzheimer's disease. Peptides. 2011;32(11):2225-2228. DOI: 10.1016/j.peptides.2011.09.019Get.

Zhu X, Cao Y, Voodg K, Steiner DF. On the processing of proghrelin to ghrelin. J Biol Chem. 2006;281(50):38867-38870. DOI: 10.1074/jbc.M607955200.

Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem. Sci. 2000;25(3):111-112. DOI: 10.1016/s0968-0004(99)01539-x.

Masumoto N, Lanyon-Hogg T, Rodgers UR, Konitsiotis AD, Magee AI, Tate EW. Membrane bound O-acyltransferases and their inhibitors. Biochem Soc Trans. 2015;43(2):246-252.DOI: 10.1042/BST20150018.

Taylor MS, Ruch TR, Hsiao P-Y, Hwang Y, Zhang P, Dai L, et al. Architectural organization of the metabolic regulatory enzyme ghrelin O-acyltransferase. J Biol Chem. 2013;288(45):32211-32228. DOI: 10.1074/jbc.M113.510313.

Buglino JA, Resh MD. Identification of conserved regions and residues within hedgehog acyltransferase critical for palmitoylation of Sonic hedgehog. PLoS One. 2010;5(6):e11195,1-10. DOI: 10.1371/journal.pone.0011195.

Taylor MS, Dempsey DR, Hwang Y, Chen Z, Chu N, Boeke JD, et al. Mechanistic analysis of ghrelin-O-acyltransferase using substrate analogs. Bioorg Chem. 2015;62:64-73. DOI: 10.1016/j.bioorg.2015.07.003.

Ma D, Wang Z, Merrikh CN, Lang KS, Lu P, Li X, et al. Crystal structure of a membrane-bound O-acyltransferase. Nature. 2018;562(7726):286-290. DOI: 10.1038/s41586-018-0568-2.

Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res. 2003;31(13):3381-3385.DOI: 10.1093/nar/gkg520.

Xu D, Jaroszewski L, Li Z, Godzik A. AIDA: ab initio domain assembly server. Nucleic Acids Res. 2014;42(W1):W308-W313. DOI: 10.1093/nar/gku369.

Heo L, Park H, Seok C. GalaxyRefine: protein structure refinement driven by side-chain repacking. Nucleic Acids Res. 2013;41(W1):W384-W388. DOI: 10.1093/nar/gkt458.

Krieger E, Joo K, Lee J, Lee J, Raman S, Thompson J, et al. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins. 2009;77(Suppl9):114-122. DOI: 10.1002/prot.22570.

Hashemi S, Sharifi A, Zareei S, Mohamedi G, Biglar M, Amanlou M. Discovery of direct inhibitor of KRAS oncogenic protein by natural products: a combination of pharmacophore search, molecular docking, and molecular dynamic studies. Res Pharm Sci. 2020;15(3):226-240. DOI: 10.4103/1735-5362.288425.

Laskowski RA. PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res. 2001;29(1):221-222. DOI: 10.1093/nar/29.1.221.

Hosseini FS, Amanlou A, Amanlou M. Tankyrase inhibitor for cardiac tissue regeneration: an in-silico approach. Iran J Pharm Res. 2021;20(4):315-328. DOI: 10.22037/ijpr.2021.115367.15339.

Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1:19-25. DOI: 10.1016/j.softx.2015.06.001.

Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, et al. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput. 2016;12(1):405-413. DOI: 10.1021/acs.jctc.5b00935.

Moose JE, Leets KA, Mate NA, Chisholm JD, Hougland JL. An overview of ghrelin O-acyltransferase inhibitors: a literature and patent review for 2010-2019. Expert Opin Ther Pat. 2020;30(8):581-593. DOI: 10.1080/13543776.2020.1776263.

Asadi M, Mohammadi-Khanaposhtani M, Hosseini FS, Gholami M, Dehpour AR, Amanlou M. Design, synthesis, and evaluation of novel racecadotril-tetrazole-amino acid derivatives as new potent analgesic agents. Res Pharm Sci. 2021;16(4):341-357. DOI:10.4103/1735-5362.319573.

Hosseini FS, Amanlou M. Anti-HCV and anti-malaria agent, potential candidates to repurpose for coronavirus infection: Virtual screening, molecular docking, and molecular dynamics simulation study. Life Sci. 2020:118205. DOI: 10.1016/j.lfs.2020.118205.

Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model. 2005;45(1):160-169. DOI: 10.1021/ci049885e.

Novick PA, Ortiz OF, Poelman J, Abdulhay AY, Pande VS. SWEETLEAD: an in silico database of approved drugs, regulated chemicals, and herbal isolates for computer-aided drug discovery. PLoS One. 2013;8(11):e79568. DOI: 10.1371/journal.pone.0079568.

Campaña MB, Irudayanathan FJ, Davis TR, McGovern-Gooch KR, Loftus R, Ashkar M, et al. The ghrelin O-acyltransferase structure reveals a catalytic channel for transmembrane hormone acylation. J Biol Chem. 2019;294(39):14166-14174. DOI:10.1074/jbc.AC119.009749.

Shoemaker SC, Ando N. X-rays in the cryo-electron microscopy era: Structural biology’s dynamic future. Biochemistry. 2018;57(3):277-285. DOI: 10.1021/acs.biochem.7b01031.

McGovern-Gooch KR, Mahajani NS, Garagozzo A, Schramm AJ, Hannah LG, Sieburg MA, et al. Synthetic triterpenoid inhibition of human ghrelin O-acyltransferase: the involvement of a functionally required cysteine provides mechanistic insight into ghrelin acylation. Biochemistry. 2017;56(7):919-931.DOI: 10.1021/acs.biochem.6b01008.

Galka CS, Hembre EJ, Honigschmidt NA, Keding SJ, Martinez-Grua MA, Plaza GR, et al. inventors; Preparation of n-acylamino acid derivatives as Preparation of n-acylamino acid derivatives as ghrelin O-acyl transferase inhibitors. USA. 2016. Pub. NO:WO/2016/168225 A1. International Application No:PCT/EP2019/027180.

Bandyopadhyay A, Cheung M, Eidam HS, Joshi H, Su D-S. inventors; Preparation of ghrelin O-acyltransferase inhibitors for treatment of metabolic disorders. UK. 2019. Pub. NO. WO/2019/149959 A1. International Application No:PCT/US2016/052770.

Godbout C, Trieselmann T, Vintonyak V, inventors; Preparation of oxadiazolopyridine derivatives for use as ghrelin O-acyl transferase (GOAT) inhibitors. Germany. 2018. NO. WO/2018/024653 A1. International Application No:PCT/EP2017/069274.

Jennings BC, Linder ME. DHHC protein S-acyltransferases use similar ping-pong kinetic mechanisms but display different acyl-CoA specificities. J Biol Chem. 2012;287(10): 7236-7245. DOI: 10.1074/jbc.M111.337246

Beevers AJ, Kukol A. Conformational flexibility of the peptide hormone ghrelin in solution and lipid membrane bound: a molecular dynamics study. J Biomol Struct Dyn. 2006;23(4):357-364. DOI: 10.1080/07391102.2006.10531231.

Fleckenstein A, Grün G, Döring HJ, Haastert HP, Tritthart H. Ethaverin, a coronary dilator with beta-receptor depressing and antiarrhythmia myocardial effects. Die Medizinische Welt. 1973;24(12):441-449. PMID: 4144783.

Jorge AP, Horst H, de Sousa E, Pizzolatti MG, Silva FR. Insulinomimetic effects of kaempferitrin on glycaemia and on 14C-glucose uptake in rat soleus muscle. Chem Biol Interact. 2004;149(2-3):89-96. DOI: 10.1016/j.cbi.2004.07.001.

Shibata T, Matsui K, Nagao K, Shinkai H, Yonemori F, Wakitani K. Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative. Eur J Pharmacol. 1999;364(2-3):211-219. DOI: 10.1016/S0014-2999(98)00832-2.

Razzaghi-Asl N, Mirzayi S, Mahnam K, Adhami V, Sepehri S. In silico screening and molecular dynamics simulations toward new human papillomavirus 16 type inhibitors. Res Pharm Sci. 2022;17(2):189-208. DOI: 10.4103/1735-5362.335177.

Mojaddami A, Sakhteman A, Fereidoonnezhad M, Faghih Z, Najdian A, Khabnadideh S, et al. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies. Res Pharm Sci. 2017;12(1):21-30. DOI: 10.4103/1735-5362.199043.


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