A computational chemistry perspective on the current status and future direction of hepatitis B antiviral drug discovery

Morgnanesi, Dante; Heinrichs, Eric J.; Mele, Anthony R.; Wilkinson, Sean R.; Zhou, Suzanne; Kulp, John L.

doi:10.1016/j.antiviral.2015.10.014

Cited by 15 publications

(12 citation statements)

References 101 publications

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“…Hepatitis is a severe liver disease with worldwide distribution [1]. There are a lot of factors that take part in the occurrence of hepatitis, such as bacteria, viruses, drugs, alcohol, parasite, chemical poisons and autoimmune [2][3][4][5]. The mainly pathological characteristics of hepatitis are hepatocyte injury, liver dysfunction and abnormal expressions of aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholinesterase (CHE), alkaline phosphatase (AP) and c-glutamyl transpeptidase (GGTP) [6,7].…”

Section: Introductionmentioning

confidence: 99%

Emodin weakens liver inflammatory injury triggered by lipopolysaccharide through elevating microRNA-145 in vitro and in vivo

Xie

Liu

2019

Artificial Cells, Nanomedicine, and Biotechnology

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Hepatitis is a severe liver disease with worldwide distribution. This study explored the antiinflammatory influence of Emodin on LPS-triggered liver injury in vitro and in vivo. In vitro, we discovered that LPS treatment triggered L-02 cell and primary hepatocyte inflammatory injury. Emodin weakened the LPS-triggered cell inflammatory injury and NF-jB pathway activation. Emodin alleviated LPS-stimulated decrease of miR-145 expression. Moreover, miR-145 participated in the regulation of pro-inflammatory factors expression and negatively regulated IRAK1. Besides, IRAK1 exert regulatory roles in the activation of NF-jB pathway. In vivo, we found that Emodin pre-treatment weakened the LPS-triggered increases of pro-inflammatory factors expression, up-regulations of AST and ALT level, liver cell apoptosis, reduction of miR-145 and enhancement of IRAK1. Our research verified that Emodin weakened LPS-triggered liver cell inflammatory injury in vitro and in vivo might be achieved by elevating miR-145, decreasing IRAK1 and then suppressing NF-jB pathway.

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Section: Introductionmentioning

confidence: 99%

Emodin weakens liver inflammatory injury triggered by lipopolysaccharide through elevating microRNA-145 in vitro and in vivo

Xie

Liu

2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…The coronavirus disease 2019 (COVID-19) disease-an infectious disease caused by the coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-poses a serious public health risk. Despite extensive efforts, of which some have included computational techniques (1,2), specific antiviral medicines to treat the widespread infection are still in critical need. In this work, we have developed an efficient simulation protocol to explore the molecular basis of fusion peptide (FP) opening of the SARS-CoV-2 spike protein (Fig.…”

Section: Introductionmentioning

confidence: 99%

Enhanced sampling protocol to elucidate fusion peptide opening of SARS-CoV-2 spike protein

Remington

McKay

Ferrell

et al. 2021

Biophysical Journal

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Large-scale conformational transitions in the spike protein S2 domain are required during host cell infection of the SARS-CoV-2 virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes due to the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a novel selection algorithm, and Markov state models to interrogate the dynamics of the S2 domain. We discovered that the conformational flexibility of the dynamic region upstream of the fusion peptide in S2 is coupled to the proteolytic cleavage state of the spike protein. These results suggest that opening of the fusion peptide likely occurs on a sub-microsecond timescale following cleavage at the S2’ site. Building on the structural and dynamical information gained to date about S2 domain dynamics, we provide proof-of-principle that a small molecule bound to a seam neighboring the fusion peptide can slow the opening of the fusion peptide, leading to a new inhibition strategy for experiments to confirm. In aggregate, these results will aid the development of drug cocktails to inhibit infections caused by SARS-CoV-2 and other coronaviruses.

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“…The importance of molecular dynamics (MD) calculations has invariably been increasing in the fields of science and technology, including chemistry, 1,2 physics, 3 biology, 4–7 virology, 8–11 and their interdisciplinary research fields 12–14 . MD calculations have additionally been applied to materials design at the molecular level 15–19 .…”

Section: Introductionmentioning

confidence: 99%

Algorithm to minimize MPI communications in the parallelized fast multipole method combined with molecular dynamics calculations

et al. 2021

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In the era of exascale supercomputers, large‐scale, and long‐time molecular dynamics (MD) calculations are expected to make breakthroughs in various fields of science and technology. Here, we propose a new algorithm to improve the parallelization performance of message passing interface (MPI)‐communication in the MPI‐parallelized fast multipole method (FMM) combined with MD calculations under three‐dimensional periodic boundary conditions. Our approach enables a drastic reduction in the amount of communication data, including the atomic coordinates and multipole coefficients, both of which are required to calculate the electrostatic interaction by using the FMM. In communications of multipole coefficients, the reduction rate of communication data in the new algorithm relative to the amount of data in the conventional one increases as both the number of FMM levels and the number of MPI processes increase. The aforementioned rate increase could exceed 50% as the number of MPI processes becomes larger for very large systems. The proposed algorithm, named the minimum‐transferred data (MTD) method, should enable large‐scale and long‐time MD calculations to be calculated efficiently, under the condition of massive MPI‐parallelization on exascale supercomputers.

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A computational chemistry perspective on the current status and future direction of hepatitis B antiviral drug discovery

Cited by 15 publications

References 101 publications

Emodin weakens liver inflammatory injury triggered by lipopolysaccharide through elevating microRNA-145 in vitro and in vivo

Emodin weakens liver inflammatory injury triggered by lipopolysaccharide through elevating microRNA-145 in vitro and in vivo

Enhanced sampling protocol to elucidate fusion peptide opening of SARS-CoV-2 spike protein

Algorithm to minimize MPI communications in the parallelized fast multipole method combined with molecular dynamics calculations

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