Novel androgen receptor full antagonists: Design, synthesis, and a docking study of glycerol and aminoglycerol derivatives that contain p-carborane cages
“…The binding of glycerol, which was conformed by ITC, might have induced the large structural difference we observed between DBM and mammalian Repeat34 domains, hinting at its potential function in modulating the structure and activity of DBM RyR. Drugs using glycerol as scaffold [66] and drug pockets rich in positive charges [67, 68] have both been reported in previous studies. Bioinformatics analysis shows that this pocket is conserved only in insects, which makes it a potential target for designing insect-specific green pesticides with the potential to fight the current resistance crisis.…”
Background
Ryanodine receptor (RyR), a calcium-release channel located in the sarcoplasmic reticulum membrane of muscles, is the target of insecticides used against a wide range of agricultural pests. Mammalian RyRs have been shown to be under the regulatory control of several kinases and phosphatases, but little is known about the regulation of insect RyRs by phosphorylation.
Results
Here we present the crystal structures of wild-type and phospho-mimetic RyR Repeat34 domain containing PKA phosphorylation sites from diamondback moth (DBM), a major lepidopteran pest of cruciferous vegetables. The structure has unique features, not seen in mammalian RyRs, including an additional α-helix near the phosphorylation loop. Using tandem mass spectrometry, we identify several PKA sites clustering in the phosphorylation loop and the newly identified α-helix. Bioinformatics analysis shows that this α-helix is only present in Lepidoptera, suggesting an insect-specific regulation. Interestingly, the specific phosphorylation pattern is temperature-dependent. The thermal stability of the DBM Repeat34 domain is significantly lower than that of the analogous domain in the three mammalian RyR isoforms, indicating a more dynamic domain structure that can be partially unfolded to facilitate the temperature-dependent phosphorylation. Docking the structure into the cryo-electron microscopy model of full-length RyR reveals that the interface between the Repeat34 and neighboring HD1 domain is more conserved than that of the phosphorylation loop region that might be involved in the interaction with SPRY3 domain. We also identify an insect-specific glycerol-binding pocket that could be potentially targeted by novel insecticides to fight the current resistance crisis.
Conclusions
The crystal structures of the DBM Repeat34 domain reveals insect-specific temperature-dependent phosphorylation sites that may regulate insect ryanodine receptor function. It also reveals insect-specific structural features and a potential ligand-binding site that could be targeted in an effort to develop green pesticides with high species-specificity.
“…The binding of glycerol, which was conformed by ITC, might have induced the large structural difference we observed between DBM and mammalian Repeat34 domains, hinting at its potential function in modulating the structure and activity of DBM RyR. Drugs using glycerol as scaffold [66] and drug pockets rich in positive charges [67, 68] have both been reported in previous studies. Bioinformatics analysis shows that this pocket is conserved only in insects, which makes it a potential target for designing insect-specific green pesticides with the potential to fight the current resistance crisis.…”
Background
Ryanodine receptor (RyR), a calcium-release channel located in the sarcoplasmic reticulum membrane of muscles, is the target of insecticides used against a wide range of agricultural pests. Mammalian RyRs have been shown to be under the regulatory control of several kinases and phosphatases, but little is known about the regulation of insect RyRs by phosphorylation.
Results
Here we present the crystal structures of wild-type and phospho-mimetic RyR Repeat34 domain containing PKA phosphorylation sites from diamondback moth (DBM), a major lepidopteran pest of cruciferous vegetables. The structure has unique features, not seen in mammalian RyRs, including an additional α-helix near the phosphorylation loop. Using tandem mass spectrometry, we identify several PKA sites clustering in the phosphorylation loop and the newly identified α-helix. Bioinformatics analysis shows that this α-helix is only present in Lepidoptera, suggesting an insect-specific regulation. Interestingly, the specific phosphorylation pattern is temperature-dependent. The thermal stability of the DBM Repeat34 domain is significantly lower than that of the analogous domain in the three mammalian RyR isoforms, indicating a more dynamic domain structure that can be partially unfolded to facilitate the temperature-dependent phosphorylation. Docking the structure into the cryo-electron microscopy model of full-length RyR reveals that the interface between the Repeat34 and neighboring HD1 domain is more conserved than that of the phosphorylation loop region that might be involved in the interaction with SPRY3 domain. We also identify an insect-specific glycerol-binding pocket that could be potentially targeted by novel insecticides to fight the current resistance crisis.
Conclusions
The crystal structures of the DBM Repeat34 domain reveals insect-specific temperature-dependent phosphorylation sites that may regulate insect ryanodine receptor function. It also reveals insect-specific structural features and a potential ligand-binding site that could be targeted in an effort to develop green pesticides with high species-specificity.
“…BA321 opened the potential for a new therapy option for males with osteoporosis that avoids musculoskeletal mass loss due to androgen deficiency [ 162 ]. In 2018, further investigations into SARMs included exploring glycerol and aminoglycerol-containing carboranes as novel androgen modulators [ 163 ]. The application of carboranes as steroid analogues was also recently applied to progesterone.…”
In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron’s emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development.
“…Similarly, the Ohta/Endo group developed carborane-derived compounds to target androgen receptor (AR). 183 , 184 The AR homodimer translocated to nucleus and bound to the androgen response elements (AREs) in DNA, after which the AR-ARE complexes interacted with the promoters to regulate the target genes ( Figure 7 A). 185 Subsequently, several carborane-containing AR ligands were developed as candidates for prostate cancer therapeutics.…”
Section: Applications Of Carboranes As Anticancer Ligandsmentioning
confidence: 99%
“… 186 , 187 , 188 The carborane cage served as a hydrophobic pharmacophore for the AR ligand binding domain (AR LBD) of antagonists ( 33 , 34 ) ( Figure 6 B). 183 , 184 Figure 7 Mechanisms and signaling pathways (A) Mechanisms of gene regulation by AR. (B) Mechanisms of gene regulation by VDR.…”
Section: Applications Of Carboranes As Anticancer Ligandsmentioning
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