Molecular Modeling Study on the Interaction Mechanism between the LRRK2 G2019S Mutant and Type I Inhibitors by Integrating Molecular Dynamics Simulation, Binding Free Energy Calculations, and Pharmacophore Modeling

Tan, Shuoyan; Zhang, Qianqian; Wang, Jun; Gao, Peng; Liu, Huanxiang; Yao, Xiaojun

doi:10.1021/acschemneuro.1c00726

Cited by 18 publications

(23 citation statements)

References 39 publications

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“…The ATP molecule interacts with Lys1906 and not with other important residues. None of the kinase domain–mutated residues forms interactions with the ATP molecule similar to the previous homology obtained structures [ 65 , 68 , 70 ]. The knowledge of the intermolecular interactions between the G2019S LRRK2 kinase domain and ATP may be critical for the development of G2019S-specific inhibitors over WT LRRK2 protein.…”

Section: Structural Biology Of Lrrk2supporting

confidence: 81%

“…Interestingly, in a parallel study, the binding mechanism of Type I LRRK2 G2019S inhibitors was revealed using molecular docking and molecular dynamics simulations following similar interactions with active-site residues. The modeling results demonstrate that hinge region residues Glu1948 and Ala1950 are critical in maintaining the intermolecular hydrogen bond interaction with the G2019S LRRK2 protein and inhibitor [ 70 ]. The gatekeeper residue Met1947 connects the N and C terminals of the kinase to form pi-sulfur interactions with the adenine ring of ATP.…”

Section: Structural Biology Of Lrrk2mentioning

confidence: 99%

“…Tan et al recently applied the molecular modeling approach on selected LRRK2 Type I inhibitors to study the detailed binding mode between the protein and ligand. The molecular dynamics simulation results reveal the key amino acids Glu1948 and Ala1950 are responsible for intermolecular hydrogen bond interactions between LRRK2 G2019S and inhibitor compounds [ 70 ]. Recent development of LRRK2 degraders using ASOs and Type I LRRK2 inhibitor scaffolds gives another hope to developing novel LRRK2 degraders which can overcome the limitations of Type I inhibitors [ 109 , 116 , 141 , 142 , 143 , 144 ].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Section: Structural Biology Of Lrrk2supporting

confidence: 81%

Section: Structural Biology Of Lrrk2mentioning

confidence: 99%

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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“…Accelrys CHARMm force field was conducted throughout the simulation, and all other parameters were set to default values in the program. Root‐mean‐square deviation (RMSD) values were analyzed at the end of the simulation (Tan et al, 2022).…”

Section: Methodsmentioning

confidence: 99%

Establishment of fingerprint and mechanism of anti‐myocardial ischemic effect of Syringa pinnatifolia

Zhang

et al. 2022

Biomedical Chromatography

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This study established the fingerprint of Syringa pinnatifolia Hemsl. (SP), analyzed the SP ingredients absorbed into the rats blood, and evaluated its anti-myocardial ischemic effect to provide a scientific basis for the follow-up development and research of SP and lay a foundation for its clinical application using ultra-performance liquid chromatography-Q Exactive-mass spectrometry and GC-MS. Myocardial infarction was induced in rat by ligating the left anterior descending branch of the rat coronary artery, and SP alcohol extract was administered to evaluate its anti-myocardial ischemic effect. We analyzed the SP ingredients absorbed into the rats blood, screened the active compounds, established a database of SP anti-myocardial ischemic targets, and explored the possible mechanism of SP in treating myocardial infarction using bioinformatics. The rats were examined using echocardiography, serum biomarkers were determined, and pathological changes were observed by histopathological examination. TUNEL staining was performed to detect the apoptotic level of cells, and Western blot and quantitative real-time polymerase chain reaction were performed to detect the expression levels of Bcl-2, Bax, and Caspase-3 in heart tissues.In the fingerprint of SP, 24 common peaks were established, and the similarity evaluation results of 10 batches of SP were all >0.9. Ultra-performance liquid chromatography-Q Exactive-mass spectrometry and GC-MS detected 17 active ingredients in the drug-containing serum, including terpenoids, flavonoids, phenols, phenylpropanoids, and phenolic acids, the most abundant of which was resveratrol.Enrichment analysis of SP targets against myocardial ischemia revealed that key candidate targets of SP were significantly enriched in multiple pathways associated with apoptosis. Resveratrol was administered to the successfully modeled rats, and the results showed that the resveratrol group significantly decreased left ventricular enddiastolic diameter and left ventricular end-systolic diameter and significantly increased ejection fraction and fractional shortening in all groups compared with the model group. Resveratrol significantly decreased the levels of creatine kinase isoenzyme and lactate dehydrogenase in serum compared to the model group (P < 0.001).Hematoxylin-eosin staining of rat myocardial tissue showed that all lesions were reduced under microscopic observation in the resveratrol group compared with the model group. Real-time polymerase chain reaction and Western blot results showed

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“…Saldaña-Rivero and co-workers used the MM-GBSA approach to explain how L858R, T790M and L858R/T790M mutations impact the binding mechanism of ATP ( Saldaña-Rivera et al, 2019 ). The popular MM/GBSA approach has been used to obtain a rough estimate of the binding free energy for a variety of complexes to explicate drug resistance ( Zhang et al, 2019 ; Tan et al, 2022 ). A mechanistic explanation linking the mutations of the protein induce changes in the conformational free-energy landscape was also investigated by using massive molecular dynamics (MD) simulations together with parallel tempering, metadynamics, and one of the best force-fields available, showing a clear shift toward the active conformation for the T790M mutant and the L858R/T790M mutant ( Sutto and Gervasio, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations

Zhou

Liu

et al. 2022

Front. Mol. Biosci.

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The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T790M mutation significantly changes the van der Waals interaction of ATP and the binding site. We also find that the favorable binding of ATP to the L858R/T790M mutant, compared with the L858R mutant, is due to a conformational change of the αC-helix, the A-loop and the P-loop of the latter induced by the T790M mutation. This change makes the interaction of ATP and P-loop, αC-helix in the L858R/T790M mutant higher than that in the L858R mutant, therefore increasing the binding affinity of ATP to EGFR. We believe the drug-resistance mechanism proposed in this study will provide valuable guidance for the design of drugs for NSCLC.

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Molecular Modeling Study on the Interaction Mechanism between the LRRK2 G2019S Mutant and Type I Inhibitors by Integrating Molecular Dynamics Simulation, Binding Free Energy Calculations, and Pharmacophore Modeling

Cited by 18 publications

References 39 publications

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Establishment of fingerprint and mechanism of anti‐myocardial ischemic effect of Syringa pinnatifolia

Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations

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