New Binding Site Conformations of the Dengue Virus NS3 Protease Accessed by Molecular Dynamics Simulation
Identifieur interne : 001068 ( Main/Exploration ); précédent : 001067; suivant : 001069New Binding Site Conformations of the Dengue Virus NS3 Protease Accessed by Molecular Dynamics Simulation
Auteurs : Hugo De Almeida [France] ; Izabela Bastos [Brésil] ; Bergman Ribeiro [France] ; Bernard Maigret [France] ; Jaime Santana [Brésil]Source :
- PLoS ONE [ 1932-6203 ] ; 2013-08-21.
Abstract
Dengue fever is caused by four distinct serotypes of the dengue virus (DENV1-4), and is estimated to affect over 500 million people every year. Presently, there are no vaccines or antiviral treatments for this disease. Among the possible targets to fight dengue fever is the viral NS3 protease (NS3PRO), which is in part responsible for viral processing and replication. It is now widely recognized that virtual screening campaigns should consider the flexibility of target protein by using multiple active conformational states. The flexibility of the DENV NS3PRO could explain the relatively low success of previous virtual screening studies. In this first work, we explore the DENV NS3PRO conformational states obtained from molecular dynamics (MD) simulations to take into account protease flexibility during the virtual screening/docking process. To do so, we built a full NS3PRO model by multiple template homology modeling. The model comprised the NS2B cofactor (essential to the NS3PRO activation), a glycine flexible link and the proteolytic domain. MD simulations had the purpose to sample, as closely as possible, the ligand binding site conformational landscape prior to inhibitor binding. The obtained conformational MD sample was clustered into four families that, together with principal component analysis of the trajectory, demonstrated protein flexibility. These results allowed the description of multiple binding modes for the Bz-Nle-Lys-Arg-Arg-H inhibitor, as verified by binding plots and pair interaction analysis. This study allowed us to tackle protein flexibility in our virtual screening campaign against the dengue virus NS3 protease
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CS 25233 - 54052 Nancy cedex</addrLine><country key="FR"></country></address><ref type="url">http://www.univ-lorraine.fr/</ref></desc></org></tutelle><tutelle name="UMR7503" active="#struct-441569" type="indirect"><org type="institution" xml:id="struct-441569" status="VALID"><idno type="ISNI">0000000122597504</idno><idno type="IdRef">02636817X</idno><orgName>Centre National de la Recherche Scientifique</orgName><orgName type="acronym">CNRS</orgName><date type="start">1939-10-19</date><desc><address><country key="FR"></country></address><ref type="url">http://www.cnrs.fr/</ref></desc></org></tutelle></tutelles></hal:affiliation><country>France</country><placeName><settlement type="city">Nancy</settlement><settlement type="city">Metz</settlement><region type="region" nuts="2">Grand Est</region><region type="old region" nuts="2">Lorraine (région)</region></placeName><orgName type="university">Université de Lorraine</orgName></affiliation></author><author><name sortKey="Santana, Jaime" sort="Santana, Jaime" uniqKey="Santana J" first="Jaime" last="Santana">Jaime Santana</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-411925" status="VALID"><orgName>Department of Cell Biology</orgName><desc><address><country key="BR"></country></address></desc><listRelation><relation active="#struct-343011" type="direct"></relation></listRelation><tutelles><tutelle active="#struct-343011" type="direct"><org type="institution" xml:id="struct-343011" status="INCOMING"><orgName>The University of Brasília</orgName><desc><address><country key="FR"></country></address></desc></org></tutelle></tutelles></hal:affiliation><country>Brésil</country></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="ISSN">1932-6203</idno><imprint><date type="datePub">2013-08-21</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dengue fever is caused by four distinct serotypes of the dengue virus (DENV1-4), and is estimated to affect over 500 million people every year. Presently, there are no vaccines or antiviral treatments for this disease. Among the possible targets to fight dengue fever is the viral NS3 protease (NS3PRO), which is in part responsible for viral processing and replication. It is now widely recognized that virtual screening campaigns should consider the flexibility of target protein by using multiple active conformational states. The flexibility of the DENV NS3PRO could explain the relatively low success of previous virtual screening studies. In this first work, we explore the DENV NS3PRO conformational states obtained from molecular dynamics (MD) simulations to take into account protease flexibility during the virtual screening/docking process. To do so, we built a full NS3PRO model by multiple template homology modeling. The model comprised the NS2B cofactor (essential to the NS3PRO activation), a glycine flexible link and the proteolytic domain. MD simulations had the purpose to sample, as closely as possible, the ligand binding site conformational landscape prior to inhibitor binding. The obtained conformational MD sample was clustered into four families that, together with principal component analysis of the trajectory, demonstrated protein flexibility. These results allowed the description of multiple binding modes for the Bz-Nle-Lys-Arg-Arg-H inhibitor, as verified by binding plots and pair interaction analysis. This study allowed us to tackle protein flexibility in our virtual screening campaign against the dengue virus NS3 protease</div></front></TEI><affiliations><list><country><li>Brésil</li><li>France</li></country><region><li>Grand Est</li><li>Lorraine (région)</li></region><settlement><li>Metz</li><li>Nancy</li></settlement><orgName><li>Université de Lorraine</li></orgName></list><tree><country name="France"><region name="Grand Est"><name sortKey="De Almeida, Hugo" sort="De Almeida, Hugo" uniqKey="De Almeida H" first="Hugo" last="De Almeida">Hugo De Almeida</name></region><name sortKey="Maigret, Bernard" sort="Maigret, Bernard" uniqKey="Maigret B" first="Bernard" last="Maigret">Bernard Maigret</name><name sortKey="Ribeiro, Bergman" sort="Ribeiro, Bergman" uniqKey="Ribeiro B" first="Bergman" last="Ribeiro">Bergman Ribeiro</name></country><country name="Brésil"><noRegion><name sortKey="Bastos, Izabela" sort="Bastos, Izabela" uniqKey="Bastos I" first="Izabela" last="Bastos">Izabela Bastos</name></noRegion><name sortKey="Santana, Jaime" sort="Santana, Jaime" uniqKey="Santana J" first="Jaime" last="Santana">Jaime Santana</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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