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Written by | Screening very large chemical libraries in November
is quite beneficial for finding ligands, and the emergence of DNA codes and virtual libraries provide a source for ligand discovery and optimization 【1-4】
。 There are more than 20 billion easily accessible molecules
in the virtual library.
These virtual libraries help discover small molecules
suitable for receptor sites, low use concentrations, high affinity potency.
Serotonin receptor 5-HT2AR has become a very interesting target
for the treatment of psychiatric disorders such as schizophrenia, depression and anxiety.
However, ligand development for 5-HT2AR and research on chemical probes have been slow because of the high specificity required and functional selectivity for signaling, which makes 5-HT2AR a therapeutically valuable but challenging target
.
Recently, the Jonathan A.
Ellman Research Group at Yale University, the Bryan L.
Roth Research Group at the University of North Carolina, the Brian K.
Shoichet Research Group at the University of California, San Francisco, the Georgios Skiniotis Research Group at Stanford University, the John J.
Irwin Research Group at the University of California, San Francisco, and the William of Duke University C.
Wetsel's research group collaborated in the publication of the Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity in Nature Through the screening of a virtual library of more than 75 million small molecule ligands, 17 molecules were preliminarily synthesized and tested, and the 5-HT2AR agonists (R)-69 and (R)-70
were found based on structural optimization.
Neither drug has psychedelic activity compared to the classic 5-HT2AR agonist, and in mouse models, both drugs have potent antidepressant activity and, at doses as low as one-fortieth, have the same efficacy
as antidepressants such as fluoxetine.
To screen for possible 5-HT2AR ligands, the authors hope to build a large library
around specific scaffolds and reactions.
The authors in the virtual library entered a wide range of functional groups
.
For the synthesis and analysis of simplified libraries, the authors involved only non-chiral and monoisomers in the virtual libraries
.
The preliminary virtual library contains 4.
3 billion compounds
.
To maximize the likelihood of hits, the authors limited the molecular mass and finally settled on an initial virtual library
of 75 million molecules.
Fig.
1 The 5-HT2AR agonist virtual library screening workflow
obtained some possible target molecules from the virtual library, and further obtained 17 high-affinity small molecules
for 5-HT2AR through structure-based optimization steps 。 Based on calcium flux measurements, the authors identified strong agonists (R)-69 and (R)-70 for 5-HT2AR with semi-maximum effective concentration values of 41 nM and 110 nM
, respectively.
Further, the authors evaluated the selectivity of 5-HT2AR agonist small molecules and found that (R)-69 and (R)-70 have higher selectivity
for 5-HT2AR than 5-HT2BR and 5-HT2CR.
Subsequently, the authors wanted to test the potency and selectivity of (R)-69 and (R)-70 in vivo activity, wondering whether the agonist drug of 5-HT2AR could exert antidepressant and anxiolytic effects
.
First, it is encouraging that both (R)-69 and (R)-70 have significant brain permeability in mouse pharmacokinetic studies, facilitating the study of their role in the
brain.
Second, the authors found that the use of (R)-69 and (R)-70 did not cause a loss of
motor stimulation activity.
To test the effects of (R)-69 and (R)-70 in a model of depression-like behavior and learning helplessness in mice, the authors used mice with a heterozygous VMAT2 heterozygous mutation of the vesicle monoamine transporter, which showed bradykinesia in the open environment, pleasure in the lack of sucrose solution, increased learned helplessness, and increased
serum corticosterone levels induced by stress, compared to wild-type controls.
In forced swimming and suspension tests, the standing time increases [5].
Tests on (R)-69 and (R)-70, as well as several other drugs, were found to have antidepressant activity
over 24 hours after administration.
In general, the authors screened 5-HT2AR agonists by establishing a large-scale virtual library, and further combined with structure-based optimization to synthesize small molecule agonist drugs, in which (R)-69 and (R)-70 have the characteristics
of low use concentration and high affinity 。 The favorable physical properties of these new agonists confer high brain permeability, and it is worth noting that both drugs have side effects such as hallucinogenicity compared to the classic 5-HT2AR agonists, and both drugs have demonstrated strong antidepressant activity
in mouse models.
In the future, custom virtual libraries will greatly expand the prospects for
small molecule drug development.
Pattern maker: Eleven
is quite beneficial for finding ligands, and the emergence of DNA codes and virtual libraries provide a source for ligand discovery and optimization 【1-4】
。 There are more than 20 billion easily accessible molecules
in the virtual library.
These virtual libraries help discover small molecules
suitable for receptor sites, low use concentrations, high affinity potency.
Serotonin receptor 5-HT2AR has become a very interesting target
for the treatment of psychiatric disorders such as schizophrenia, depression and anxiety.
However, ligand development for 5-HT2AR and research on chemical probes have been slow because of the high specificity required and functional selectivity for signaling, which makes 5-HT2AR a therapeutically valuable but challenging target
.
Recently, the Jonathan A.
Ellman Research Group at Yale University, the Bryan L.
Roth Research Group at the University of North Carolina, the Brian K.
Shoichet Research Group at the University of California, San Francisco, the Georgios Skiniotis Research Group at Stanford University, the John J.
Irwin Research Group at the University of California, San Francisco, and the William of Duke University C.
Wetsel's research group collaborated in the publication of the Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity in Nature Through the screening of a virtual library of more than 75 million small molecule ligands, 17 molecules were preliminarily synthesized and tested, and the 5-HT2AR agonists (R)-69 and (R)-70
were found based on structural optimization.
Neither drug has psychedelic activity compared to the classic 5-HT2AR agonist, and in mouse models, both drugs have potent antidepressant activity and, at doses as low as one-fortieth, have the same efficacy
as antidepressants such as fluoxetine.
To screen for possible 5-HT2AR ligands, the authors hope to build a large library
around specific scaffolds and reactions.
The authors in the virtual library entered a wide range of functional groups
.
For the synthesis and analysis of simplified libraries, the authors involved only non-chiral and monoisomers in the virtual libraries
.
The preliminary virtual library contains 4.
3 billion compounds
.
To maximize the likelihood of hits, the authors limited the molecular mass and finally settled on an initial virtual library
of 75 million molecules.
Fig.
1 The 5-HT2AR agonist virtual library screening workflow
obtained some possible target molecules from the virtual library, and further obtained 17 high-affinity small molecules
for 5-HT2AR through structure-based optimization steps 。 Based on calcium flux measurements, the authors identified strong agonists (R)-69 and (R)-70 for 5-HT2AR with semi-maximum effective concentration values of 41 nM and 110 nM
, respectively.
Further, the authors evaluated the selectivity of 5-HT2AR agonist small molecules and found that (R)-69 and (R)-70 have higher selectivity
for 5-HT2AR than 5-HT2BR and 5-HT2CR.
Subsequently, the authors wanted to test the potency and selectivity of (R)-69 and (R)-70 in vivo activity, wondering whether the agonist drug of 5-HT2AR could exert antidepressant and anxiolytic effects
.
First, it is encouraging that both (R)-69 and (R)-70 have significant brain permeability in mouse pharmacokinetic studies, facilitating the study of their role in the
brain.
Second, the authors found that the use of (R)-69 and (R)-70 did not cause a loss of
motor stimulation activity.
To test the effects of (R)-69 and (R)-70 in a model of depression-like behavior and learning helplessness in mice, the authors used mice with a heterozygous VMAT2 heterozygous mutation of the vesicle monoamine transporter, which showed bradykinesia in the open environment, pleasure in the lack of sucrose solution, increased learned helplessness, and increased
serum corticosterone levels induced by stress, compared to wild-type controls.
In forced swimming and suspension tests, the standing time increases [5].
Tests on (R)-69 and (R)-70, as well as several other drugs, were found to have antidepressant activity
over 24 hours after administration.
In general, the authors screened 5-HT2AR agonists by establishing a large-scale virtual library, and further combined with structure-based optimization to synthesize small molecule agonist drugs, in which (R)-69 and (R)-70 have the characteristics
of low use concentration and high affinity 。 The favorable physical properties of these new agonists confer high brain permeability, and it is worth noting that both drugs have side effects such as hallucinogenicity compared to the classic 5-HT2AR agonists, and both drugs have demonstrated strong antidepressant activity
in mouse models.
In the future, custom virtual libraries will greatly expand the prospects for
small molecule drug development.
Original link:
https://doi.
org/10.
1038/s41586-022-05258-z
Pattern maker: Eleven
References
1.
Gloriam, D.
E.
Bigger is better in virtual drug screens.
Nature 566, 193–194 (2019).
2.
Lyu, J.
et al.
Ultra-large library docking for discovering new chemotypes.
Nature 566, 224–229 (2019).
3.
Gorgulla, C.
et al.
An open-source drug discovery platform enables ultra-large virtual screens.
Nature 580, 663–668 (2020).
4.
Stein, R.
M.
et al.
Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.
Nature 579, 609–614 (2020).
5.
Roth, B.
L.
, Willins, D.
L.
, Kristiansen, K.
& Kroeze, W.
K.
Activation is hallucinogenic and antagonism is therapeutic: role of 5-HT2A receptors in atypical antipsychotic drug actions.
Neuroscientist 5, 254–262 (1999)
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