Molecular Docking and ADME Analysis of L-Phe -L-Tyr Dipeptide

Hypertension is a serious risk factor for various diseases. Therefore, lowering and preventing high blood pressure is a significant issue. Blockage of the renin-angiotensin-aldosterone system (RAAS), which controls blood pressure, is important to reduce blood pressure and consequently reduce symptoms of heart failure. This blockage can be carried out by angiotensin-converting enzyme (ACE) and angiotensin II receptor blockers (ARBs). The phenylalanyltyrosine (H-Phe-Tyr-OH, Phe-Tyr, L-Phe-L-Tyr, L-phenylalanyl-L-tyrosine) dipeptide examined in this study is an important structure that shows blood pressure lowering properties. For this reason, the potential of the peptide to be an ACE inhibitor or ARB was investigated. The molecular activity of the Phe-Tyr dipeptide was compared with antihypertensive drugs using theoretical calculations. Molecular docking method, one of these theoretical methods, has a considerable process in illuminating biochemical processes by investigating the interactions of drugs (ligands) with targeted receptors. In this theoretical study, molecular docking analyses of H-Phe-Tyr-OH dipeptide with ACE and Angiotensin II type 1 receptor (AT1R) were implemented. The interaction types and interaction regions of the peptide were also determined in comparison with drug molecules (Captopril, Enalapril, Telmisartan and Eprosartan) that are ACE inhibitors and ARBs. Lastly, ADME (absorption, distribution, metabolism, and excretion) analysis of the H-Phe-Tyr-OH dipeptide was also performed to estimate its drug potential. In this study, the pharmacokinetic properties of Phe-Tyr dipeptide and its mechanism of action with ACE and AT1R were investigated for the first time by molecular docking and ADME calculations.

Keywords:

Antihypertensive, Peptide docking, ADME,

PDF

___

[1] Laurent, S., Antihypertensive drugs, Pharmacol. Res., 124 (2017) 116-125.
[2] Hill R.D., Vaidya P.N., Angiotensin II Receptor Blockers (ARB). In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL), (2022).
[3] Shahoud, J. S., Terrence S., and Narothama R.A., Physiology, arterial pressure regulation. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL), (2022).
[4] Kritsi, E., Matsoukas, M.T., Potamitis, C., Karageorgos, V., Detsi, A., Magafa, V., Liapakis, G., Mavromoustakos, T., Zoumpoulakis, P., Exploring new scaffolds for angiotensin II receptor antagonism, Bioorg. Med. Chem., 24 (18) (2016) 4444-4451.
[5] Amaya, J.A.G., Cabrera, D.Z., Matallana, A.M., Arevalo, K.G., Guevara-Pulido, J., In-silico design of new enalapril analogs (ACE inhibitors) using QSAR and molecular docking models, Inform. Med. Unlocked., 19 (2020) 100336.
[6] Herman, L.L., Padala, S.A., Ahmed, I., Bashir, K., Angiotensin converting enzyme inhibitors (ACEI). In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL), (2022).
[7] Wang, Z., Cheng, C., Yang, X., Zhang, C., L-phenylalanine attenuates high salt-induced hypertension in Dahl SS rats through activation of GCH1-BH4, PLoS One, 16 (4) (2021) e0250126.
[8] Sved, A.F., Fernstrom, J.D., Wurtman, R.J., Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats, Proc. Natl. Acad. Sci. U.S.A., 76 (7) (1979) 3511-3514.
[9] Suetsuna, K., Maekawa, K., Chen, J.R., Antihypertensive effects of Undaria pinnatifida (wakame) peptide on blood pressure in spontaneously hypertensive rats, J. Nutr. Biochem., 15 (5) (2004) 267-272.
[10] Kecel-Gündüz, S., Budama-Kilinc, Y., Cakir Koc, R., Kökcü, Y., Bicak, B., Aslan, B., Özel, A.E., Computational design of Phe-Tyr dipeptide and preparation, characterization, cytotoxicity studies of Phe-Tyr dipeptide loaded PLGA nanoparticles for the treatment of hypertension, J. Biomol. Struct. Dyn., 36 (11) (2018) 2893-2907.
[11] Khan, T., Lawrence, A.J., Azad, I., Raza, S., Khan, A.R., Molecular Docking Simulation with Special Reference to Flexible Docking Approach, JSM Chem., 6 (1) (2018) 1053-1057.
[12] [Meng, X.Y., Zhang, H.X., Mezei, M., Cui, M., Molecular docking: a powerful approach for structure-based drug discovery, Curr. Comput.-Aided Drug Des., 7 (2) (2011) 146-157.
[13] McConkey, B.J., Sobolev, V., Edelman, M., The performance of current methods in ligand–protein docking, Curr. Sci., 83 (7) (2002) 845-856.
[14] Bıçak, B., Gündüz, S.K., Kökcü, Y., Özel, A.E., Akyüz, S., Molecular docking and molecular dynamics studies of L-glycyl-L-glutamic acid dipeptide,Bilgesci, 3 (1) (2019) 1-9.
[15] Lakhrissi, Y., Rbaa, M., Tuzun, B., Hichar, A., Anouar, E.H., Ounine, K., Almalki, F., Hadda, T.B., Zarrouk, A., Lakhrissi, B., Synthesis, structural confirmation, antibacterial properties and bio-informatics computational analyses of new pyrrole based on 8-hydroxyquinoline, J. Mol. Struct., 1259 (2022) 132683.
[16] Jayarajan, R., Satheeshkumar, R., Kottha, T., Subbaramanian, S., Sayin, K., Vasuki, G., Water mediated synthesis of 6-amino-5-cyano-2-oxo-N-(pyridin-2-yl)-4-(p-tolyl)-2H-[1, 2′-bipyridine]-3-carboxamide and 6-amino-5-cyano-4-(4-fluorophenyl)-2-oxo-N-(pyridin-2-yl)-2H-[1, 2′-bipyridine]-3-carboxamide–An experimental and computational studies with non-linear optical (NLO) and molecular docking analyses, Spectrochim. Acta A Mol. Biomol. Spectrosc., 229 (2020) 117861.
[17] Lehtola, S., Automatic algorithms for completeness‐optimization of Gaussian basis sets, J. Comput. Chem., 36 (5) (2015) 335-347.
[18] Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Petersson G.A., Nakatsuji H., et.al., Gaussian 16 Rev. B.01, Wallingford, CT, 2016.
[19] Trott, O., Arthur J. O., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem., 31 (2) (2010) 455-461.
[20]Biovia Discovery Studio, Available at: https://www.3ds.com/products-services/biovia/products/molecular-modeling-simulation/biovia-discovery-studio/. Retrieved May 14, 2022.
[21] Daina, A., Michielin, O., Zoete, V., SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep., 7 (1) (2017) 1-13.
[22] Pagadala, N.S., Syed, K., Tuszynski, J., Software for molecular docking: a review, Biophys. Rev., 9 (2) (2017) 91-102.
[23]Andújar-Sánchez, M., Cámara-Artigas, A., Jara-Pérez, V., A calorimetric study of the binding of lisinopril, enalaprilat and captopril to angiotensin-converting enzyme, Biophys. Chem., 111 (2) (2004) 183-189.
[24]Pina, A.S., Roque, A.C.A., Studies on the molecular recognition between bioactive peptides and angiotensin‐converting enzyme, J. Mol. Recognit., 22 (2) (2009) 162-168.
[25]Wang, X., Chen, H., Fu, X., Li, S., Wei, J., A novel antioxidant and ACE inhibitory peptide from rice bran protein: Biochemical characterization and molecular docking study, Lwt, 75 (2017) 93-99.
[26]Amaya, J.A.G., Cabrera, D.Z., Matallana, A.M., Arevalo, K.G., Guevara-Pulido, J., In-silico design of new enalapril analogs (ACE inhibitors) using QSAR and molecular docking models, Inform. Med. Unlocked., 19 (2020) 100336.
[27] Dalkas, G.A., Marchand, D., Galleyrand, J.C., Martinez, J., Spyroulias, G.A., Cordopatis, P., Cavelier, F., Study of a lipophilic captopril analogue binding to angiotensin I converting enzyme, J. Pept. Sci., 16 (2) (2010) 91-97.
[28]Singh, K.D., Unal, H., Desnoyer, R., Karnik, S.S., Divergent spatiotemporal interaction of angiotensin receptor blocking drugs with angiotensin type 1 receptor, J. Chem. Inf. Model., 58 (1) (2018) 182-193.
[29]Sant’Anna, L.S., Merlugo, L., Ehle, C.S., Limberger, J., Fernandes, M.B., Santos, M.C., Mendez, A.S.L., Paula, F.R., Moreira, C.M., Chemical composition and hypotensive effect of Campomanesia xanthocarpa, J. Evid. Based Complementary Altern. Med., 2017 (2017).
[30]Zhang, H., Unal, H., Desnoyer, R., Han, G.W., Patel, N., Katritch, V., Karnik, S.S., Cherezov, V., Stevens, R.C., Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor, J. Biol. Chem., 290 (49) (2015) 29127-29139.
[31] Lipinski, C.A., Lead-and drug-like compounds: the rule-of-five revolution, Drug Discov. Today Technol., 1 (4) (2004) 337-341.
[32]Carpenter, T.S., Kirshner, D.A., Lau, E.Y., Wong, S.E., Nilmeier, J.P., Lightstone, F.C., A method to predict blood-brain barrier permeability of drug-like compounds using molecular dynamics simulations, Biophys. J., 107 (3) (2014) 630-641.
[33]Mannhold, R., Kubinyi, H., Folkers, G., Molecular drug properties: measurement and prediction, Weinheim, Wiley-VCH, 37 (2008) 111-123.
[34]Lynch, T., Neff, A.P., The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects, Am. Fam. Physician., 76 (3) (2007) 391-396.
[35]Ji, D., Xu, M., Udenigwe, C.C., Agyei, D., Physicochemical characterisation, molecular docking, and drug-likeness evaluation of hypotensive peptides encrypted in flaxseed proteome, Curr. Res. Food Sci., 3 (2020) 41-50.