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Serine Hydrolase Targeted Library

12 000 compounds
for cherry picking

Serine hydrolases are important class of enzymes which include lipases, esterases, thioesterases, amidases, peptidases and proteases. They belong to one of the largest and most diverse classes of enzymes found in nature and represent ~1% of all proteins in mammalians playing vital roles in such pathophysiological processes as blood clotting, digestion, nervous system signalling, inflammation and cancer.

Despite the fact that pharmaceutical industry avoids developing therapeutics that form covalent bonds with protein targets, several commercialized serine hydrolase inhibitors as well as promising drug candidates contain electrophilic chemical groups that interact covalently with the serine nucleophile in the active site of their targets (Fig. 1).

General description of generation

The main criteria of the selection was presence of the electrophilic group (e.g., CN, epoxide, carbonyl, etc.) which can provide the key interaction with serine in the active site. Next we estimated the 3D shape of the molecules and compared them by throughput docking with the volume of the active sites taken from X-ray data of several serine hydrolases. The compounds that did not fit to the active site were withdrawn.

Representative examples of molecules in the Library

Figure 1. Representative examples of commercialized serine hydrolase covalent inhibitors and examples of functional groups that usually bind in the active site.

On the other hand we applied several MedChem structural filters in order to remove unattractive groups/moieties, trivial and “banal” chemotypes, and “saturate” the library with compounds with novel scaffolds, Fsp3-rich frameworks and peptidomimetic moieties. In addition special diversity filters were applied in order to remove repeated chemotypes and assure the high level of diversity for the final library (Fig. 2).

Representative examples of molecules in the Library

Figure 2. Representative examples of compounds from serine hydrolase targeted library.

Parameters Range
MW < 500
ClogP < 5
TPSA < 130 Å2
Hb Donors < 5
Hb Acceptors < 10
RotBonds < 8

Molecular properties of the Library

Mol Weight logP
Hb donors Hb acceptors
Rot. Bonds PSA

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