In Silico Docking Analysis of A-type Proanthocyanidins to α-Glucosidase Constructed by Correlation with in Vitro Bioassay
Journal of Drug Design and Medicinal Chemistry
Volume 5, Issue 4, December 2019, Pages: 47-60
Received: Nov. 21, 2019; Accepted: Dec. 7, 2019; Published: Dec. 23, 2019
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Sheau Ling Ho, Department of Chemical & Materials Engineering, Chinese Culture University, Taipei, Taiwan, ROC
Yili Lin, School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
Shengfa Tsai, School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
Shoeisheng Lee, School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC
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The type A proanthocyanidins (2−8) with (2β→O→7, 4β→8) interflavane linkage, isolated from Machilus philippinensis, have been found to possess inhibitory activity against α-glucosidase (EC from Bacillus stearothermophilus). To rationalize such activity, computer assisted docking of these compounds and the positive control, acarbose, on the conformation model of α-glucosidase (AG), built by using human intestinal maltase glucoamylase as a template, was undertaken in this study. The result showed good correlation between IC50 values and docking scores, expressed as binding energy (ΔG), obtained from London (trimatch)-refinement (forcefield AffinityΔG) mode. Among these isolates, the most potent aesculitannin B (2) (IC50 3.5μM) showed the best docking score (ΔG -21.48 kcal/mol). Being interested in clarification of structure and activity relationship, virtual screening on the related compounds, including the de-unit III homologs of 2−8 (i.e., nor- series) and additional 13 stereoisomers of the trimeric 2 at the C-2 and C-3 positions of units II and III, was further carried out. This docking study indicated the de-unit III homologs of 2−8 did not have better binding energies than 2. As for the trimers, 3-entC, 3C-entE, 3ent-C, 3C, and 3ent, showed comparable docking score to 2. The verification of this virtual screening was partially done by evaluating the inhibitory activity of the dimeric 2-nor-ent, 3-nor, 3-nor-ent, and iso-2-nor-ent, isolated from peanut skins, against α-glucosidase. Of these, iso-2-nor-ent, the only proanthocyanidin with (2β→O→7, 4β→6) interflavane linkage, showed the best activity (IC50 9.72 μM). Their simulation profiles of docking score also displayed a reasonable qualitative consistency with the overall trend of the bioassay results. This study demonstrates that virtual screening using this built model to search α-glucosidase inhibitors is facile and feasible and peanut skin might be used as a hypoglycemic food.
α-Glucosidase, Proanthocyanidins, Bioassay, Molecular Docking, Proanthocyanidin Homologs, Peanut Skin
To cite this article
Sheau Ling Ho, Yili Lin, Shengfa Tsai, Shoeisheng Lee, In Silico Docking Analysis of A-type Proanthocyanidins to α-Glucosidase Constructed by Correlation with in Vitro Bioassay, Journal of Drug Design and Medicinal Chemistry. Vol. 5, No. 4, 2019, pp. 47-60. doi: 10.11648/j.jddmc.20190504.11
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S. Chiba (1997) Molecular mechanism in α-glucosidase and glucoamylase. Bioscience, Biotechnology, and Biochemistry 61, 1233−1239.
Nichols, B. L., J. Eldering, S. Avery, D. Hahn, A. Quaroni, and E. Sterchi (1998). Human small intestinal maltase-glucoamylase cDNA cloning homology to sucrase-isomaltase. Journal of Biological Chemistry 273, 3076−3081.
G. Semenza and S. Auricchio, “Small intestinal disaccharidases,” in The Metabolic Basis of Inherited Disease, 6th ed. C. R. Scriver, A. L. Beaudet, A. S. Sly, D. Valle, J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, Eds. New York: McGraw-Hill, 1989, pp 2975−2997.
M. Hanefeld (1998) The role of acarbose in the treatment of non-insulin-dependent diabetes mellitus. Journal of Diabetes Complications 12, 228−237.
Khan, M., M. Yousaf, A. Wadood, M. Junaid, M. Ashraf, U. Alam, et al. (2014) Discovery of novel oxindole derivatives as potent α-glucosidase inhibitors. Bioorganic and Medicinal Chemistry 22, 3441−3448.
Khan, K. M., F. Rahim, A. Wadood, N. Kosar, M. Taha, S. Lalani, et al. (2014) Synthesis and molecular docking studies of potent α-glucosidase inhibitors based on biscoumarin skeleton. European Journal of Medicinal Chemistry 81, 245−252.
Chang, C. C., S. L. Ho, and S. S. Lee (2015) Acylated glucosylflavones as α-glucosidase inhibitors from Tinospora crispa leaf. Bioorganic and Medicinal Chemistry 23, 3388−3396.
Lin, H. C. and S. S. Lee (2010) Proanthocyanidins from the Leaves of Machilus philippinensis. Journal of Natural Products 73, 1375−1380.
Lou, H., Y. Ymazaki, T. Sasaki, M. Uchida, H. Tanaka, and S. Oka (1999) A-type proanthocyanidins from peanut skins. Phytochemistry 51, 297−308.
Berman, H. M., J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, and P. E. Bourne (2000) The Protein Data Bank. Nucleic Acids Research 28, 235−242.
Vilar, S., G. Cozza, and S. Moro (2008) Medicinal chemistry and the molecular operating environment (MOE): application of QSAR and molecular docking to drug discovery. Current Topics of Medicinal Chemistry 8, 1555−1572.
Davies, G. and B. Henrissat (1995) Structures and mechanisms of glycosyl hydrolases. Structure 3, 853−859.
Lovering, A. L., S. S. Lee, Y. W. Kim, S. G. Withers, and N. C. J. Strynadka (2005) Mechanistic and structural analysis of a family 31 alpha-glycosidase and its glycosyl-enzyme intermediate. Journal of Biological Chemistry 280, 2105−2115.
Sim, L., K. Jayakanthan, S. Mohan, R. Nasi, B. D. Johnston, B. M. Pinto, and D. R. Rose (2010) New glucosidase inhibitors from an Ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata. Biochemistry 49, 443−451.
P. Labute (2009) Protonate3D: assignment of ionization states and hydrogen coordinates to macromolecular structures. Proteins 75, 187−205.
(a) T. A. Halgren (1996) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. Journal of Computation Chemistry 17, 490−519; (b) ibid. (1999) MMFF VI. MMFF94s option for energy minimization studies. ibid. 20, 720−729.
Santos-Buelgaa, C., Kolodzieij, H., and Treutter, D. (1995) Procyanidin trimers possessing a doubly linked structure from Aesculus hippocastanum. Phytochemistry 38, 499−504.
Zhang, C. F., Sun, Q. S., Wang, Z. T., and Hattori, M. (2003) One new A-type proanthocyanidin trimer from Lindera aggregate (Sims) Kosterm. Chinese Chemical Letters 14, 1033−1036.
Yoshimizu, M., Tajima, Y., Matsuzawa, F., Aikawa, S., Iwamoto, K., Kobayashi, T. et al. (2008) Binding parameters and thermodynamics of the interaction of iminosugars with a recombinant human acid alpha-glucosidase (alglucosidase alfa): insight into the complex formation mechanism. Clinica Chimica Acta 391, 68−73.
Hermans, M. M. P., M. A. Kroos, J. van Beeurnen, B. A. Oostra, and A. J. Reuser (1991) Human lysosomal -glucosidase characterization of the catalytic site. Journal of Biological Chemistry 266, 13507−13512.
Sugawara, K, K. Ohno, S. Saito, and Sakuraba H (2008) Structural characterization of mutant alpha-galactosidases causing Fabry disease. Journal of Human Genetics 53, 812−824.
Sugawara, K., S. Saito, M. Sekijima, K. Ohno, Y. Tajima, and M. A. Kroos (2009) Structural modeling of mutant -glucosidases resulting in a processing/transport defect in Pompe disease. Journal of Human Genetics 54, 324−330.
Perica, T. and C. Chothia (2010) Ubiquitin-molecular mechanisms for recognition of different structures. Current Opinion in Structural Biology 20, 367−376.
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