Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation

Rayevsky, Alexey; Sirokha, Dmytro; Samofalova, Dariia; Lozhko, D. M.; Gorodna, Olexandra; Prokopenko, Inga; Livshits, Liudmyla

doi:10.3390/life11070659

Cited by 7 publications

(2 citation statements)

References 46 publications

(52 reference statements)

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“…The level of pore clearance and the overall geometry were tested with a multifunctional tool Caver Analyst 2.0 (Masaryk University. Czech Republic), which is incredibly convenient for the identification of internal implied movement [85][86][87][88][89].…”

Section: Simulationmentioning

confidence: 99%

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors

Platonov,

Maximyuk,

Rayevsky

et al. 2024

IJMS

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Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1–ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.

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Section: Simulationmentioning

confidence: 99%

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors

Platonov,

Maximyuk,

Rayevsky

et al. 2024

IJMS

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“…For the inner cavity and entrance tunnel volatility assessment and demonstration of the effects of the STARD8 p.R887C and p.S993N substitutions, CAVER Analyst 2.0 software was applied [15][16][17][18]. The radius of the inner cavity and the radius of the entrance tunnels were calculated for every snapshot of the trajectory.…”

Section: Simulationsmentioning

confidence: 99%

Mutations in STARD8 (DLC3) May Cause 46,XY Gonadal Dysgenesis

Sirokha,

Rayevsky,

Gorodna

et al. 2023

Sex Dev

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Introduction: 46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testis integrity during its development. Methods: We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed. Results: These simulations revealed the full rearrangement of the p.R887C substitution containing the helix upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype. Conclusion: Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis.

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