Access block,known as exit block or boarding,is defined as a situation in which patients who are admitted or planned for admission remain in the emergency department(ED)as they are unable to be transferred to an inpat...Access block,known as exit block or boarding,is defined as a situation in which patients who are admitted or planned for admission remain in the emergency department(ED)as they are unable to be transferred to an inpatient unit within a reasonable time frame(no longer than 8 hours).[1,2]Access block often occurs due to insufficient hospital capacity and is a major issue in emergency medicine.[3]展开更多
This study utilizes the enzyme-substrate complex theory to predict the clinical efficacy of COVID-19 treatments at the biological systems level, using molecular docking stability indicators. Experimental data from the...This study utilizes the enzyme-substrate complex theory to predict the clinical efficacy of COVID-19 treatments at the biological systems level, using molecular docking stability indicators. Experimental data from the Protein Data Bank and molecular structures generated by AlphaFold 3 were used to create macromolecular complex templates. Six templates were developed, including the holo nsp7-nsp8-nsp12 (RNA-dependent RNA polymerase) complex with dsRNA primers (holo-RdRp-RNA). The study evaluated several ligands—Favipiravir-RTP, Remdesivir, Abacavir, Ribavirin, and Oseltamivir—as potential viral RNA polymerase inhibitors. Notably, the first four of these ligands have been clinically employed in the treatment of COVID-19, allowing for comparative analysis. Molecular docking simulations were performed using AutoDock 4, and statistical differences were assessed through t-tests and Mann-Whitney U tests. A review of the literature on COVID-19 treatment outcomes and inhibitors targeting RNA polymerase enzymes was conducted, and the inhibitors were ranked according to their clinical efficacy: Remdesivir > Favipiravir-RTP > Oseltamivir. Docking results obtained from the second and third templates aligned with clinical observations. Furthermore, Abacavir demonstrated a predicted efficacy comparable to Favipiravir-RTP, while Ribavirin exhibited a predicted efficacy similar to that of Remdesivir. This research, focused on inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase, establishes a framework for screening AI-generated drug templates based on clinical outcomes. Additionally, it develops a drug screening platform based on molecular docking binding energy, enabling the evaluation of novel or repurposed drugs and potentially accelerating the drug development process.展开更多
Currently, no clinically approved therapeutic drugs specifically target dengue virus infections. This study aims to evaluate the potential of antiviral drugs originally developed for other purposes as viable candidate...Currently, no clinically approved therapeutic drugs specifically target dengue virus infections. This study aims to evaluate the potential of antiviral drugs originally developed for other purposes as viable candidates for combating dengue virus. The RNA-elongating NS5-NS3 complex is a critical molecular structure responsible for dengue virus replication. Using the cryo-electron microscopy (Cryo-EM) structures available in the Protein Data Bank and AlphaFold 3 predictions, this study simulated the replication complexes of dengue virus serotypes 1, 2, 3, and 4. The RNA-dependent RNA polymerase (RdRp) domain of the NS5 protein within the NS5-NS3 complex was selected as the molecular docking template. Molecular docking simulations were conducted using AutoDock4. Seven small molecules—AT-9010, RK-0404678, Oseltamivir, Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin—were assessed for binding affinity by calculating their binding energies, where lower values indicate stronger molecular interactions. Based on published data, antiviral replication assays were conducted for the four dengue virus serotypes. AT-9010 and RK-0404678 were used as benchmarks for antiviral replication efficacy, while Oseltamivir served as the control group. The Mann-Whitney U test was employed to classify the clinical antiviral candidates—Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin. Results demonstrated that among the four small molecules, Favipiravir-RTP exhibited the highest binding affinity with the RdRp domain of the NS5-NS3 complex across all four dengue virus serotypes. Statistical classification revealed that in five simulated scenarios—including the four virus serotypes and Cryo-EM structural data—Favipiravir-RTP shared three classifications with the benchmark molecule AT-9010. Based on these findings, Favipiravir-RTP, a broad-spectrum antiviral agent, shows potential as a therapeutic option for inhibiting dengue virus replication. However, further clinical trials are necessary to validate their efficacy in humans.展开更多
基金supported by the Project of Science and Technology Commission of Jiading,Shanghai(JDKW-2016-W03)the Scientific Research Projects of the Shanghai Municipal Health Commission for Youths(20204Y0016)+1 种基金the National Natural Science Foundation of China(72174041)。
文摘Access block,known as exit block or boarding,is defined as a situation in which patients who are admitted or planned for admission remain in the emergency department(ED)as they are unable to be transferred to an inpatient unit within a reasonable time frame(no longer than 8 hours).[1,2]Access block often occurs due to insufficient hospital capacity and is a major issue in emergency medicine.[3]
文摘This study utilizes the enzyme-substrate complex theory to predict the clinical efficacy of COVID-19 treatments at the biological systems level, using molecular docking stability indicators. Experimental data from the Protein Data Bank and molecular structures generated by AlphaFold 3 were used to create macromolecular complex templates. Six templates were developed, including the holo nsp7-nsp8-nsp12 (RNA-dependent RNA polymerase) complex with dsRNA primers (holo-RdRp-RNA). The study evaluated several ligands—Favipiravir-RTP, Remdesivir, Abacavir, Ribavirin, and Oseltamivir—as potential viral RNA polymerase inhibitors. Notably, the first four of these ligands have been clinically employed in the treatment of COVID-19, allowing for comparative analysis. Molecular docking simulations were performed using AutoDock 4, and statistical differences were assessed through t-tests and Mann-Whitney U tests. A review of the literature on COVID-19 treatment outcomes and inhibitors targeting RNA polymerase enzymes was conducted, and the inhibitors were ranked according to their clinical efficacy: Remdesivir > Favipiravir-RTP > Oseltamivir. Docking results obtained from the second and third templates aligned with clinical observations. Furthermore, Abacavir demonstrated a predicted efficacy comparable to Favipiravir-RTP, while Ribavirin exhibited a predicted efficacy similar to that of Remdesivir. This research, focused on inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase, establishes a framework for screening AI-generated drug templates based on clinical outcomes. Additionally, it develops a drug screening platform based on molecular docking binding energy, enabling the evaluation of novel or repurposed drugs and potentially accelerating the drug development process.
文摘Currently, no clinically approved therapeutic drugs specifically target dengue virus infections. This study aims to evaluate the potential of antiviral drugs originally developed for other purposes as viable candidates for combating dengue virus. The RNA-elongating NS5-NS3 complex is a critical molecular structure responsible for dengue virus replication. Using the cryo-electron microscopy (Cryo-EM) structures available in the Protein Data Bank and AlphaFold 3 predictions, this study simulated the replication complexes of dengue virus serotypes 1, 2, 3, and 4. The RNA-dependent RNA polymerase (RdRp) domain of the NS5 protein within the NS5-NS3 complex was selected as the molecular docking template. Molecular docking simulations were conducted using AutoDock4. Seven small molecules—AT-9010, RK-0404678, Oseltamivir, Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin—were assessed for binding affinity by calculating their binding energies, where lower values indicate stronger molecular interactions. Based on published data, antiviral replication assays were conducted for the four dengue virus serotypes. AT-9010 and RK-0404678 were used as benchmarks for antiviral replication efficacy, while Oseltamivir served as the control group. The Mann-Whitney U test was employed to classify the clinical antiviral candidates—Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin. Results demonstrated that among the four small molecules, Favipiravir-RTP exhibited the highest binding affinity with the RdRp domain of the NS5-NS3 complex across all four dengue virus serotypes. Statistical classification revealed that in five simulated scenarios—including the four virus serotypes and Cryo-EM structural data—Favipiravir-RTP shared three classifications with the benchmark molecule AT-9010. Based on these findings, Favipiravir-RTP, a broad-spectrum antiviral agent, shows potential as a therapeutic option for inhibiting dengue virus replication. However, further clinical trials are necessary to validate their efficacy in humans.
