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Library Genesis
Library Genesis
Without a shadow of a doubt, the papers in the above hotlinks provide most important data when it comes to the identification and optimization of selective, duel and non-selective opiate agonists as well as high-potency mu ligands.
Fig 1 of the first paper shows the relative spatial position and orientation (RPO) of the key moieties. You will notice that for mu agonists, the paper identifies:
1) 2x hydrogen bond acceptors (HBA)
2) positive ionizable point (PI)
3) ring aromatic group (RA)
This is a limitation as it doesn't identify the SECOND RA (ring aromatic), generally required to achieve very high potency. The second paper DOES identify this second ring.
If you employ the RPO and devise a sufficiently large and varied training set, you will discover that even the most bizarre high-potency ligands fid into these simple rules. However, their is a SIXTH binding site that appears to require pi-bonding and yet does not require a RA. Examples of this are allyl prodine & 14-cinnamyloxycodone although some early synthetic opioids such as alimadol and even the Bentley compounds may have stumbled upon this, The latter may seem an odd example but their are a number of compounds in the class in which the dihydro derivatives are significantly LESS potent.
With the above, it's now possible to state with >98% certainty that any compound with:
1) Biosteric minimum small enough to fid into mu receptor
2) Physical properties (RO5)
3) Ability to cross BBB
WILL be an active opioid.
NB the training-sets are listed from compounds with the highest affinity down to those with the lowest affinity.
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