IN SILICO STUDIES ON DIACYL DERIVATIVES OF PHLOROGLUCINOL TO ENHANCE PHARMACODYNAMIC AND PHARMACOKINETIC PROFILES OF 2,4,6-TRIHYDROXY-3-GERANYL-ACETOPHENONE
Keywords:2,4,6-trihydroxy-3-geranylacetophenone, Lipoxygenase, AUTODOCK, SWISS MODEL, Drug likeness properties
Objective: The purpose of this study was to evaluate the LOX inhibitory activity, and predict the drug likeness properties of designed diacyl derivatives of phloroglucinol, using in silico method.
Methods: The designed derivatives were subjected to molecular docking using AUTODOCK while the receptor used in this study was built from SWISS MODEL. Drug likeness properties of the derivatives were calculated by online programs i.e. MOLINSPIRATION and PreADMET.
Results: Molecular docking study revealed that designed tHGA derivative with four-carbon chain length exhibited the best binding affinity with the docking scores of -7.26kcal/mol. Three types of binding interactions were observed between the derivatives and the receptor site i.e H-bonding, hydrophobic and Van der Waals interactions. The important amino acid residues involved in H-bonding were Gln495 and Gln697, while other amino acid residues, such as Leu754 and Ile 553, were involved in the Van der Waals interaction. The designed tHGA derivatives were mainly stabilized through hydrophobic interactions with His499, His504, Ile538, Phe557 and Val750. In silico physicochemical calculations predicted that all the designed derivatives passed the Lipinski’s Rule of 5, and have good human intestinal absorption property (HIA>70%). Further, all the designed derivatives showed moderate central nervous system absorption (0.6<BBB<2.0), except for the derivative with a longer (5-Cs) chain length.
Conclusion: The findings of the present study suggested that changing the acyl and geranyl side chains of the natural product molecule, tHGA, into two acyl bearing side chains, will improve its pharmacodynamic and pharmacokinetic profiles.
WHO | Asthma; 2019. Available from: https://www.who.int/respiratory/asthma/en/. [Last accessed on 05 Nov 2020]
Radmark OP. The molecular biology and regulation of 5-lipoxygenase. Am J Respir Crit 2000;161:S11-5.
Liu M, Yokomizo T. The role of leukotrienes in allergic diseases. Allergol Int 2015;64:17-26.
Tokuyama S, Nakamoto K. Pain as modified by polyunsaturated fatty acids. In: Omega-3 fatty acids in brain and neurological health. Academic Press; 2014. p. 131-46.
Eleftheriadis N, Poelman H, Leus NG, Honrath B, Neochoritis CG, Dolga A, et al. Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties. Eur J Med Chem 2016;122:786-801.
Wisastra R, Ghizzoni M, Boltjes A, Haisma HJ, Dekker FJ. Anacardic acid derived salicylates are inhibitors or activators of lipoxygenases. Bioorg Med Chem 2012;20:5027-32.
Dahlen SE. Treatment of asthma with antileukotrienes: first line or last resort therapy? Eur J Pharmacol 2006;533:40-56.
Gilbert NC, Barlett SG, Waight MT, Neau DB, Boeglin WE, Brash AR, et al. The structure of human 5-lipoxygenase. Science 2011;331:217-9.
Skrzypczak Jankun E, Zhou K, Jankun J. Inhibition of lipoxygenase by (-)-epigallocatechin gallate: X-ray analysis at 2.1 Å reveals degradation of EGCG and shows soybean LOX-3 complex with EGC instead. Int J Mol Med 2003;12:415-20.
Shaari K, Suppaiah V, Lam KW, Stanlas J, Tejo BA, Israf DA, et al. Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase. Bioorg Med Chem 2011;19:6340-7.
Ismail N, Jambari N, Zareen S, Akhtar M, Shaari K, Zamri Saad M, et al. A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice. Toxicol Appl Pharm 2012;259:257-62.
Ng CH, Rullah K, Aluwi MFFM, Abas F, Lam KW, Ismail SI, et al. Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor. Molecules 2014;19:11645-59.
Ng CH, Rullah K, Abas F, Lam KW, Ismail SI, Jamaludin F, et al. Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) as a potent LOX inhibitor: synthesis, structure-activity relationship (SAR) study, and computational assignment. Molecules 2018;23:2509.
Mohamed MM, Jusril NA, Adenan MI, Ng KW. Molecular docking based on in silico screening of nci diversity sets for potent inhibitors of apobec3a enzyme. Int J Med Toxicol Forensic Med 2020;23:138-44.
Dirar AI, Waddad AY, Mohamed MA, Mohamed MS, Osman WJ, Mohammed MS, et al. In silico pharmacokinetics and molecular docking of three leads isolated from Tarconanthus camphoratus L. Int J Pharm Pharm 2016;8:71-7.
Ochieng PJ, Sumaryada T, Okun D. Molecular docking and pharmacokinetic prediction of herbal derivatives as maltase-glucoamylase inhibitor. Asian J Pharm Clin Res 2017;10:392-8.
Thakur A. Designing of potential new estrogen antagonists for treatment of Endometriosis: designing of ligands, molecular docking, activity, ADME and Toxicity prediction study. Int J Pharm Pharm 2013;5:451-5.
Banert K, Seifert J. Steric hindrance classified: treatment of isothiocyanatoallene with secondary amines bearing bulky substituents to generate 2-aminothiazoles. Org Chem Front 2019;6:3517-22.
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 Delivery Rev 1997;23:3-25.
Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using caco-2 cells. Eur J Pharm Sci 2000;10:195–204.
Van de Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based design: optimization of drug absorption and pharmacokinetics. J Med Chem 2001;44:1313–33.
Ilieva Y, Kokanova Nedialkova Z, Nedialkov P, Momekov G. In silico ADME and drug-likeness evaluation of a series of cytotoxic polyprenylated acylphloroglucinols, isolated from Hypericum annulatum morris subsp. annulatum. Bulg Chem Commun 2018;50:193-9.
Walker MA. Novel tactics for designing water-soluble molecules in drug discovery. Expert Opin Drug Discovery 2014;9:1421-33.
Clark DE. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of bloodbrain barrier penetration. J Pharm Sci 1999;88:807–14.
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615-23.
Feher M, Schmidt JM. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 2003;43:218-27.
Haupt VJ, Daminelli S, Schroeder M. Drug promiscuity in PDB: protein binding site similarity is key. PLoS One 2013;8:e65894.
Kumar K, R Giri A, Nadendla RR. In silico ADME profiling of CDK9 inhibitors. J Sci Res Pharm 2018;7:30-4.
Zhao YH, Le J, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, et al. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 2001;90:749–84.
Bohnert T, Gan L. Plasma protein binding: from discovery to development. J Pharm Sci 2013;102:2953-94.