Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation and Molecular Dynamics Simulation Studies
Identifieur interne : 002093 ( Main/Exploration ); précédent : 002092; suivant : 002094Inhibitors of SARS-3CLpro: Virtual Screening, Biological Evaluation and Molecular Dynamics Simulation Studies
Auteurs : Prasenjit Mukherjee ; Falgun Shah ; Prashant Desai ; Mitchell AverySource :
- Journal of chemical information and modeling [ 1549-9596 ] ; 2011.
Descripteurs français
- KwdFr :
- Concentration inhibitrice 50, Conception de médicament, Conformation des protéines, Cysteine endopeptidases (), Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Interface utilisateur, Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Simulation de dynamique moléculaire, Solvants (), Virus du SRAS (enzymologie), Évaluation préclinique de médicament ().
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Inhibiteurs de protéases.
- Concentration inhibitrice 50, Conception de médicament, Conformation des protéines, Cysteine endopeptidases, Inhibiteurs de protéases, Interface utilisateur, Protéines virales, Simulation de dynamique moléculaire, Solvants, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Cysteine Endopeptidases (chemistry), Drug Design, Drug Evaluation, Preclinical (methods), Inhibitory Concentration 50, Molecular Dynamics Simulation, Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Protein Conformation, SARS Virus (enzymology), Solvents (chemistry), User-Computer Interface, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Cysteine Endopeptidases, Protease Inhibitors, Solvents, Viral Proteins.
- enzymology : SARS Virus.
- methods : Drug Evaluation, Preclinical.
- chemical , pharmacology : Protease Inhibitors.
- Drug Design, Inhibitory Concentration 50, Molecular Dynamics Simulation, Protein Conformation, User-Computer Interface.
Abstract
SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CLpro, a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic target against SARS. A combined ligand and structure based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.
Url:
DOI: 10.1021/ci1004916
PubMed: 21604711
PubMed Central: 3929308
Affiliations:
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Le document en format XML
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xml:lang="fr"><term>Concentration inhibitrice 50</term><term>Conception de médicament</term><term>Conformation des protéines</term><term>Cysteine endopeptidases</term><term>Inhibiteurs de protéases</term><term>Interface utilisateur</term><term>Protéines virales</term><term>Simulation de dynamique moléculaire</term><term>Solvants</term><term>Évaluation préclinique de médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P3">SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL<sup>pro</sup>, a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic target against SARS. A combined ligand and structure based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multi nanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.</p></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Avery, Mitchell" sort="Avery, Mitchell" uniqKey="Avery M" first="Mitchell" last="Avery">Mitchell Avery</name><name sortKey="Desai, Prashant" sort="Desai, Prashant" uniqKey="Desai P" first="Prashant" last="Desai">Prashant Desai</name><name sortKey="Mukherjee, Prasenjit" sort="Mukherjee, Prasenjit" uniqKey="Mukherjee P" first="Prasenjit" last="Mukherjee">Prasenjit Mukherjee</name><name sortKey="Shah, Falgun" sort="Shah, Falgun" uniqKey="Shah F" first="Falgun" last="Shah">Falgun Shah</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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