Discovery of novel diarylpyrimidines as potent HIV-1 NNRTIs by investigating the chemical space of a less explored "hydrophobic channel".
Identifieur interne : 000C92 ( Main/Exploration ); précédent : 000C91; suivant : 000C93Discovery of novel diarylpyrimidines as potent HIV-1 NNRTIs by investigating the chemical space of a less explored "hydrophobic channel".
Auteurs : Zhongxia Zhou [République populaire de Chine] ; Tao Liu ; Dongwei Kang ; Zhipeng Huo ; Gaochan Wu ; Dirk Daelemans ; Erik De Clercq ; Christophe Pannecouque ; Peng Zhan ; Xinyong LiuSource :
- Organic & biomolecular chemistry [ 1477-0539 ] ; 2018.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Agents antiVIH (toxicité), Conception de médicament, Humains, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Inhibiteurs de la transcriptase inverse (toxicité), Interactions hydrophobes et hydrophiles, Lignée cellulaire tumorale, Mutation, Pyrimidines (), Pyrimidines (pharmacologie), Pyrimidines (synthèse chimique), Pyrimidines (toxicité), Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure moléculaire, Transcriptase inverse du VIH (), Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (génétique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- génétique : Transcriptase inverse du VIH.
- pharmacologie : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Pyrimidines.
- synthèse chimique : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Pyrimidines.
- toxicité : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Pyrimidines.
- Agents antiVIH, Conception de médicament, Humains, Inhibiteurs de la transcriptase inverse, Interactions hydrophobes et hydrophiles, Lignée cellulaire tumorale, Mutation, Pyrimidines, Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, Structure moléculaire, Transcriptase inverse du VIH, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Anti-HIV Agents (toxicity), Binding Sites, Cell Line, Tumor, Drug Design, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (chemistry), HIV Reverse Transcriptase (genetics), HIV-1 (drug effects), Humans, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation, Molecular Structure, Mutation, Pyrimidines (chemical synthesis), Pyrimidines (chemistry), Pyrimidines (pharmacology), Pyrimidines (toxicity), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Reverse Transcriptase Inhibitors (toxicity), Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , chemistry : Anti-HIV Agents, HIV Reverse Transcriptase, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , genetics : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Pyrimidines, Reverse Transcriptase Inhibitors.
- chemical , toxicity : Anti-HIV Agents, Pyrimidines, Reverse Transcriptase Inhibitors.
- drug effects : HIV-1.
- Binding Sites, Cell Line, Tumor, Drug Design, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation, Molecular Structure, Mutation, Structure-Activity Relationship.
Abstract
A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTI complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against the HIV-1 wild-type (WT) strain with EC50 values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV). Among them, two most promising compounds Z10 (EC50 = 3 nM) and Z13 (EC50 = 3 nM) showed equivalent potency against the HIV-1 WT strain to the reference drugs efavirenz (EFV, EC50 = 3 nM) and ETV (EC50 = 3 nM). Notably, Z13 also showed the most potent activity against HIV-1 mutant strains including K103N (EC50 = 10 nM), E138K (EC50 = 22 nM) and RES056 (EC50 = 0.935 μM). Against mutant strains Y181C, Y188L and F227L + V106A, Z17 showed double-digit nanomolar inhibitory activity with EC50 values 27 nM, 98 nM and 30 nM, respectively. The structure-activity relationships (SARs) and molecular docking studies provided important clues for further molecular elaboration. Collectively, this study provides useful information to guide lead optimization and drug discovery via the exploration of this seldom investigated region.
DOI: 10.1039/c7ob02828h
PubMed: 29349445
Affiliations:
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populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Tao" sort="Liu, Tao" uniqKey="Liu T" first="Tao" last="Liu">Tao Liu</name></author><author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name></author><author><name sortKey="Huo, Zhipeng" sort="Huo, Zhipeng" uniqKey="Huo Z" first="Zhipeng" last="Huo">Zhipeng Huo</name></author><author><name sortKey="Wu, Gaochan" sort="Wu, Gaochan" uniqKey="Wu G" first="Gaochan" last="Wu">Gaochan Wu</name></author><author><name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name></author><author><name sortKey="De Clercq, Erik" 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Sites</term><term>Cell Line, Tumor</term><term>Drug Design</term><term>HIV Reverse Transcriptase (antagonists & inhibitors)</term><term>HIV Reverse Transcriptase (chemistry)</term><term>HIV Reverse Transcriptase (genetics)</term><term>HIV-1 (drug effects)</term><term>Humans</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term><term>Mutation</term><term>Pyrimidines (chemical synthesis)</term><term>Pyrimidines (chemistry)</term><term>Pyrimidines (pharmacology)</term><term>Pyrimidines (toxicity)</term><term>Reverse Transcriptase Inhibitors (chemical synthesis)</term><term>Reverse Transcriptase Inhibitors (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Reverse Transcriptase Inhibitors (toxicity)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Agents antiVIH (synthèse chimique)</term><term>Agents antiVIH (toxicité)</term><term>Conception de médicament</term><term>Humains</term><term>Inhibiteurs de la transcriptase inverse ()</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Inhibiteurs de la transcriptase inverse (synthèse chimique)</term><term>Inhibiteurs de la transcriptase inverse (toxicité)</term><term>Interactions hydrophobes et hydrophiles</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Pyrimidines ()</term><term>Pyrimidines (pharmacologie)</term><term>Pyrimidines (synthèse chimique)</term><term>Pyrimidines (toxicité)</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Transcriptase inverse du VIH ()</term><term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term><term>Transcriptase inverse du VIH (génétique)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyrimidines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>HIV Reverse Transcriptase</term><term>Pyrimidines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyrimidines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyrimidines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term><term>Inhibiteurs de la transcriptase inverse</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term><term>Inhibiteurs de la transcriptase inverse</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Agents antiVIH</term><term>Inhibiteurs de la transcriptase inverse</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Cell Line, Tumor</term><term>Drug Design</term><term>Humans</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term><term>Mutation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Conception de médicament</term><term>Humains</term><term>Inhibiteurs de la transcriptase inverse</term><term>Interactions hydrophobes et hydrophiles</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Pyrimidines</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Transcriptase inverse du VIH</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A new series of diarylpyrimidines (DAPYs) were designed, synthesized and evaluated as novel HIV-1 NNRTIs to further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), guided by the comprehensive analysis of X-ray structural biology data of HIV-1 RT/NNRTI complexes and molecular modeling. Encouragingly, most of the synthesized DAPYs were found to be active against the HIV-1 wild-type (WT) strain with EC<sub>50</sub> values ranging from 3 nM to 63 nM, and displayed significantly reduced cytotoxicity compared with etravirine (ETV) and rilpivirine (RPV). Among them, two most promising compounds Z10 (EC<sub>50</sub> = 3 nM) and Z13 (EC<sub>50</sub> = 3 nM) showed equivalent potency against the HIV-1 WT strain to the reference drugs efavirenz (EFV, EC<sub>50</sub> = 3 nM) and ETV (EC<sub>50</sub> = 3 nM). Notably, Z13 also showed the most potent activity against HIV-1 mutant strains including K103N (EC<sub>50</sub> = 10 nM), E138K (EC<sub>50</sub> = 22 nM) and RES056 (EC<sub>50</sub> = 0.935 μM). Against mutant strains Y181C, Y188L and F227L + V106A, Z17 showed double-digit nanomolar inhibitory activity with EC<sub>50</sub> values 27 nM, 98 nM and 30 nM, respectively. The structure-activity relationships (SARs) and molecular docking studies provided important clues for further molecular elaboration. Collectively, this study provides useful information to guide lead optimization and drug discovery via the exploration of this seldom investigated region.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><noCountry><name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><name sortKey="Huo, Zhipeng" sort="Huo, Zhipeng" uniqKey="Huo Z" first="Zhipeng" last="Huo">Zhipeng Huo</name><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><name sortKey="Liu, Tao" sort="Liu, Tao" uniqKey="Liu T" first="Tao" last="Liu">Tao Liu</name><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name><name sortKey="Wu, Gaochan" sort="Wu, Gaochan" uniqKey="Wu G" first="Gaochan" last="Wu">Gaochan Wu</name><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Zhou, Zhongxia" sort="Zhou, Zhongxia" uniqKey="Zhou Z" first="Zhongxia" last="Zhou">Zhongxia Zhou</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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