Compound CID 9998128 Is a Potential Multitarget Drug for Alzheimer's Disease

ACS Chemical Neuroscience
Nguyen Quoc ThaiZuzana Gazova

Abstract

We have probed small molecule compound CID 9998128 as a potential multitarget drug for the Alzheimer's disease (AD) using in silico and in vitro experiments. By all-atom simulation and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, we have demonstrated that this compound strongly binds to both amyloid β42 (Aβ42) fibrils and β-secretase, and the van der Waals interaction dominates over the electrostatic interaction in binding affinity. A detailed analysis at the atomic level revealed that indazole in CID 99998128 structure made a major contribution to instability of all studied complexes. In vitro experiments have shown that CID 9998128 inhibits the Aβ42 amyloid fibrillization and is capable to clear Aβ42 fibrils. Moreover, the compound dose-dependently decreases β-site amyloid precursor protein cleaving enzyme (BACE-1) activity with EC50 value in micromolar range. Thus, our study has revealed that CID 9998128 is a good candidate for AD treatment through preventing production of Aβ peptides and degrading their aggregates. For drug design, we predict that the chemical structure of potent AD multitarget inhibitors should not contain indazole.

References

Nov 28, 2002·Advanced Drug Delivery Reviews·Robert Vassar
Dec 10, 2002·Neurobiology of Aging·Ashley I Bush
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Nov 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Thorsten LührsRoland Riek
Jan 25, 2007·Nature Reviews. Molecular Cell Biology·Christian Haass, Dennis J Selkoe
Jan 10, 2008·Journal of Medicinal Chemistry·Andrea CavalliCarlo Melchiorre
Jul 18, 2008·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Stephen SallowayJeffrey L Cummings
Oct 7, 2008·Journal of Molecular Biology·Mingfeng Yang, David B Teplow
Jan 30, 2009·Protein Science : a Publication of the Protein Society·Li Ling LeeMatthew P DeLisa
Mar 17, 2009·Science·Giuseppe Di FedeFabrizio Tagliavini
Jan 12, 2010·Journal of Alzheimer's Disease : JAD·M Paul Murphy, Harry LeVine
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Aug 13, 2011·Journal of Chemical Information and Modeling·Trang Truc NguyenMai Suan Li
Nov 30, 2011·Journal of Neurochemistry·Arun K GhoshJordan Tang
Mar 13, 2012·Journal of Molecular Biology·Samuel I A CohenTuomas P J Knowles
Jul 25, 2012·BMC Research Notes·Alan W Sousa da Silva, Wim F Vranken
Aug 11, 2012·The Journal of Physical Chemistry. B·Son Tung Ngo, Mai Suan Li
Feb 27, 2013·Chembiochem : a European Journal of Chemical Biology·Francesco AttanasioEnrico Rizzarelli
Sep 18, 2013·ACS Chemical Neuroscience·Man Hoang VietPhilippe Derreumaux
Feb 22, 2014·Lancet Neurology·Riqiang Yan, Robert Vassar
Dec 23, 2011·The Open Biotechnology Journal·Bradley NeddenriepDavid A Moffet
May 23, 2014·Current Neuropharmacology·Kris Simone Tranches Dias, Claudio Viegas
Jun 21, 2014·ACS Chemical Neuroscience·Man Hoang VietMai Suan Li
Jan 7, 2015·Current Opinion in Structural Biology·Andrew J Doig, Philippe Derreumaux
Mar 20, 2015·Chemical Reviews·Jessica Nasica-LabouzePhilippe Derreumaux
May 6, 2015·Nature Structural & Molecular Biology·Yiling XiaoYoshitaka Ishii
Mar 31, 2016·EMBO Molecular Medicine·Dennis J Selkoe, John Hardy
Jun 3, 2016·Frontiers in Neuroscience·Mercedes UnzetaJosé Marco-Contelles
Jun 29, 2016·Physical Chemistry Chemical Physics : PCCP·Zuzana BednarikovaZuzana Gazova
Oct 21, 2016·ACS Chemical Neuroscience·Pham Dinh Quoc HuyMai Suan Li
Jul 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Marielle Aulikki WältiRoland Riek
Oct 8, 2016·Nanoscale·Yuliang ZhangYuri L Lyubchenko
Oct 28, 2016·Protein Science : a Publication of the Protein Society·Martín Carballo-Pacheco, Birgit Strodel

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Citations

Feb 4, 2021·ACS Chemical Neuroscience·Yehong GongQingwen Zhang
Aug 31, 2021·Frontiers in Molecular Biosciences·Edward KingRay Luo

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