Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study

Chen, Qingqing; Wang, Yan; Shi, Shanshan; Li, Kaihang; Zhang, Ling; Gao, Jian

doi:10.3390/ijms20215410

Cited by 20 publications

(15 citation statements)

References 26 publications

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“…The AZD1208 compound used as a pan‐Pim inhibitor in the present investigation was shown to be a potent inducer of cytochrome P450 3A4 (CYP3A4) after multiple dosing in recent early phase clinical trials, leading to accelerated drug clearance and unfavorable pharmacodynamics that precluded ongoing development, despite evidence of biologic activity (22). This issue has not been reported for alternative agents, of greater potency, for which clinical trials are ongoing in hematologic malignancy (48–50) and which, subject to safety data, may yet provide logical repurposing opportunities for RA.…”

Section: Discussionmentioning

confidence: 99%

Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis

Maney

Lemos

Barron-Millar

et al. 2021

Arthritis & Rheumatology

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Objective As well as being an established oncoprotein and therapeutic target in cancer, proviral integration site for Moloney murine leukemia virus 1 (Pim‐1) is implicated in human autoimmunity. This study was undertaken to investigate Pim‐1 and its family members as potential therapeutic targets in early rheumatoid arthritis (RA). Methods A flow cytometry assay for PIM1 transcript measurement in peripheral blood mononuclear cells from patients with early arthritis was validated and applied as a biomarker of Pim‐1 activity at the cellular level. Synovial protein expression was similarly determined by multiplex immunofluorescence in tissue samples from untreated RA patients and non‐RA disease controls. Functional consequences of Pim kinase family manipulation in freshly isolated CD4+ T cells from these individuals were ascertained, along with the impact of Pim inhibition on mice with collagen‐induced arthritis (CIA). Results The percentage of circulating CD4+ T cells positive for PIM1 transcript by flow cytometry proved a faithful surrogate for gene expression and was significantly higher in patients with early RA than in those with other diseases. Pim‐1 protein levels were similarly up‐regulated in synovial CD4+ T cells from patients with early RA. Ex vivo, exposure of T cell receptor–stimulated early RA CD4+ T cells to Pim kinase inhibitors restrained their activation and proliferative capacity. Diminished production of proinflammatory cytokines (interferon‐γ and interleukin‐17) and an expanded CD25highFoxP3+ Treg cell fraction were also observed in exposed versus unexposed cells. Finally, administration of Pim inhibitors robustly limited arthritis progression and cartilage destruction in CIA. Conclusion Our findings indicate that Pim kinases are plausible therapeutic targets in a readily identifiable subgroup of patients with early RA. Repurposing of Pim inhibitors for this disease should be considered.

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Section: Discussionmentioning

confidence: 99%

Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis

Maney

Lemos

Barron-Millar

et al. 2021

Arthritis & Rheumatology

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“…To calculate the binding free energies of the four PLproinhibitor complexes, MM/GBSA calculation was conducted via the following Eq. (1) as described in previous studies [17][18][19]:…”

Section: Mm/gbsa Calculation and Mm/gbsa Free Energy Decomposition Analysismentioning

confidence: 99%

Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) calculation

et al. 2020

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COVID-19 is spreading in a global pandemic that is endangering human life and health. Therefore, there is an urgent need to target COVID-19 to find effective treatments for this emerging acute respiratory infection. Viral Papain-Like cysteine protease (PLpro), similar to papain and the cysteine deubiquitinase enzyme, has been a popular target for coronavirus inhibitors, as an indispensable enzyme in the process of coronavirus replication and infection of the host. Combined structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) free energy calculation approaches were utilized for identification of PLpro inhibitors. Four compounds (F403_0159, F112_0109, G805_0497, D754_0006) with diverse chemical scaffolds were retrieved as hits based on docking score and clustering analysis. Molecular dynamics simulations indicated that the contribution of van der Waals interaction dominated the binding free energies of these compounds, which may be attributed to the hydrophobicity of active site of PLpro from COVID-19. Moreover, all four compounds formed conservative hydrogen bonds with the residues Asp164, Gln269, and Tyr273. We hoped that these four compounds might represent the promising chemical scaffolds for further development of novel PLpro inhibitors against COVID-19. Electronic supplementary material The online version of this article (10.1007/s11224-020-01665-y) contains supplementary material, which is available to authorized users.

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“…With the aim of calculating the binding free energy, the calculation of MM/GBSA was carried out by using MM/GBSA in AMBER 12 software via the following equation ( Kollman et al, 2000 ; Chen Q. et al, 2019 ; An et al, 2020 ; Shi et al, 2021 ) .

…”

Section: Methodsmentioning

confidence: 99%

Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin

Geng

et al. 2021

Front. Mol. Biosci.

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The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of “lip” and “gate” loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.

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Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study

Cited by 20 publications

References 26 publications

Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis

Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis

Discovery of small molecule PLpro inhibitor against COVID-19 using structure-based virtual screening, molecular dynamics simulation, and molecular mechanics/Generalized Born surface area (MM/GBSA) calculation

Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin

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