Exploring the resistance-developing mutations on Ryanodine receptor in diamondback moth and binding mechanism of its activators using computational study

Autor: S. K. Jalali, Thiruvengadam Venkatesan, Thangaraj Sindhu, Gandhi R. Gracy, Anil Rai
Rok vydání: 2017
Předmět:
Zdroj: Biochemical Engineering Journal. 121:59-72
ISSN: 1369-703X
DOI: 10.1016/j.bej.2017.01.013
Popis: Insect Ryanodine receptor (RyR) is an intracellular calcium release channels that play a key role in calcium signaling in numerous cell types. Targeting Ryanodine receptor is considered as efficient treatment option for the control of diamondback moth, Plutella xylostella, an important pest of cruciferous crops. The present study was carried out to identify potential RyR modulators through pharmacophore modeling and virtual screening. A total of 23 experimentally proven activators of RyR were used in the development of pharmacophore model. The resulting pharmacophore consisted of one hydrogen bond acceptor site (A), one hydrophobic feature site (H) and three aromatic ring sites (R). The model AHRRR was used as a query to find effective activators through database screening and AHRRR was validated to check its reliability using enrichment calculations. ADME properties were predicted to confirm the safety profile of the identified virtual hits. Furthermore, a structural modeling approach combining computational mutagenesis, induced fit docking, MM/GBSA and DFT calculations was used to evaluate the binding mode and structural basis of the two activators screened from pharmacophore-based virtual screening. Thus, the results could provide more knowledge on the activation of RyR and helpful in the development of more potent insecticides to overcome diamide insecticide resistance.
Databáze: OpenAIRE
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