{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:08:04Z","timestamp":1787162884475,"version":"build-2736575974"},"reference-count":22,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T00:00:00Z","timestamp":1539820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Some point mutations in \u03b2-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of \u03b1-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for \u03b2-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein\u2013ligand docking and molecular dynamics simulations. We found that the activity cliff between \u03b1-1-C-heptyl-DAB and \u03b1-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic\/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.<\/jats:p>","DOI":"10.3390\/molecules23102683","type":"journal-article","created":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T10:55:41Z","timestamp":1539860141000},"page":"2683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Design of a New \u03b1-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for \u03b2-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation"],"prefix":"10.3390","volume":"23","author":[{"given":"Izumi","family":"Nakagome","sequence":"first","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-1085","authenticated-orcid":false,"given":"Noriyuki","family":"Yamaotsu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Yoshida","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichiro","family":"Ozawa","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Hirono","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4242","DOI":"10.1074\/jbc.M511110200","article-title":"Analyses of variant acid beta-glucosidases: Effects of Gaucher disease mutations","volume":"281","author":"Liou","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.cbpa.2007.05.035","article-title":"Gaucher disease","volume":"11","author":"Butters","year":"2007","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1021\/bi9002265","article-title":"Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability","volume":"48","author":"Lieberman","year":"2009","journal-title":"Biochemistry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1021\/jm301557k","article-title":"Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases","volume":"56","author":"Boyd","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"573","DOI":"10.4155\/fmc.13.14","article-title":"Glucocerebrosidase inhibitors for the treatment of Gaucher disease","volume":"5","author":"Trapero","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0165-6147(03)00158-5","article-title":"A contradictory treatment for lysosomal storage disorders: Inhibitors enhance mutant enzyme activity","volume":"24","author":"Fan","year":"2003","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.chembiol.2005.09.007","article-title":"Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles","volume":"12","author":"Sawkar","year":"2005","journal-title":"Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15428","DOI":"10.1073\/pnas.192582899","article-title":"Chemical chaperones increase the cellular activity of N370S beta -glucosidase: A therapeutic strategy for Gaucher disease","volume":"99","author":"Sawker","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1111\/j.1742-4658.2006.05410.x","article-title":"Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients","volume":"273","author":"Chang","year":"2006","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1463-1326.2006.00701.x","article-title":"N-Butyldeoxynojirimycin causes weight loss as a result of appetite suppression in lean and obese mice","volume":"10","author":"Priestman","year":"2008","journal-title":"Diabetes Obes. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.2147\/TCRM.S6865","article-title":"Review of miglustat for clinical management in Gaucher disease type 1","volume":"4","author":"Ficicioglu","year":"2008","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1111\/j.1742-4658.2010.07588.x","article-title":"The Pharmacological Chaperone Isofagomine Increases Activity of the Gaucher Disease L444P Mutant Form of \u03b2-Glucosidase","volume":"277","author":"Khanna","year":"2010","journal-title":"FEBS J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1039\/c1ob05200d","article-title":"Cyclodextrin-mediated crystallization of acid \u03b2-glucosidase in complex with amphiphilic bicyclic nojirimycin analogues","volume":"9","author":"Brumshtein","year":"2011","journal-title":"Org. Biomol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7450","DOI":"10.1002\/anie.200502662","article-title":"Rational design and synthesis of highly potent beta-glucocerebrosidase inhibitors","volume":"44","author":"Zhu","year":"2005","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1039\/C5OB02223A","article-title":"Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease","volume":"14","author":"Kato","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1074\/jbc.M110.150433","article-title":"X-ray and biochemical analysis of N370S mutant human acid \u03b2-glucosidase","volume":"286","author":"Wei","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nchembio850","article-title":"Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease","volume":"3","author":"Lieberman","year":"2007","journal-title":"Nat. Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1016\/j.bmc.2014.02.057","article-title":"Docking and SAR studies of calystegines: Binding orientation and influence on pharmacological chaperone effects for Gaucher\u2019s disease","volume":"22","author":"Kato","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1021\/ct900587b","article-title":"Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field","volume":"6","author":"Shivakumar","year":"2010","journal-title":"J. Chem. Theory Comput."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/j.1747-0285.2010.00951.x","article-title":"Probing the alpha-helical structural stability of stapled p53 peptides: Molecular dynamics simulations and analysis","volume":"75","author":"Guo","year":"2010","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bowers, K.J., Chow, E., Xu, H., Dror, R.O., Eastwood, M.P., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Moraesm, M.A., and Sacerdotim, F.D. (2006, January 11\u201317). Scalable algorithms for molecular dynamics simulations on commodity clusters. Presented at the 2006 ACM\/IEEE conference on Supercomputing, Tampa, FL, USA.","DOI":"10.1145\/1188455.1188544"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:26:29Z","timestamp":1760196389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,18]]},"references-count":22,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["molecules23102683"],"URL":"https:\/\/doi.org\/10.3390\/molecules23102683","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,18]]}}}