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Nuclear Receptor Focused Library

8 000 compounds

Nuclear receptors are a large superfamily of transcription factors involved in numerous important physiological functions as well as play a crucial role in many pathological processes, such as cancer, diabetes, rheumatoid arthritis, asthma or hormone-resistance syndromes.

We have adopted several approaches to the design of library of potential NR-ligands.

Receptor-based approach (RBA) relies on molecular docking of compounds from Enamine screening collection into receptor 3D structures. After the docking the obtained protein-ligand complex structures were processed using post-docking geometry-based filters to select those which exhibit best-fitting binding modes. The filters impose empirically defined constraints on location of a ligand in the binding site, such as distance from the key binding site points to the nearest ligand atom, occupation of certain critical regions of the binding pocket volume, and contact surface area. This filtering allows to discard quickly massive amounts of complex structures containing irrelevant binding poses and select the compounds capable of resembling binding modes of native ligands.

a)Superposition of compound Z368598474 (black) and partial antagonist Genistein (green) in the binding site of Human β-Estrogen receptorb)

Figure 1. Examples of docking results on different NR-targets:

(a) Superposition of compound Z368598474 (black) and partial antagonist Genistein (green) in the binding site of Human β-Estrogen receptor.

(b) Superposition of compound Z1444087034 and agonist AZ242 in the binding site of γ-PPAR.

Ligand based approach included search by “hot spots”: motifs/functional groups which are expected to play a key role in the interaction (Fig. 2). An extended descriptor set was identified for the several series of recently reported NR modulators. Novel chemotypes were carefully selected to contain scaffolds/key moieties similar to those found in literature. On the other hand we applied versatile similarity criteria (e.g. structural, pharmacophore) to select diverse structures which correspond to known NR-ligands.

Illustration of compound selection by hot-spots and similarity criteria: analogues of Ragaglitazar

Figure 2. Illustration of compound selection by hot-spots and similarity criteria:  analogues of Ragaglitazar (α/γ-PPAR agonist).

Molecular properties of the library

The most of NR ligands are small lipophilic molecules that easily penetrate biological membranes therefore the molecules with appropriate molecular parameters (ClogP < 5, PSA < 130, MW < 500, Hb Acceptors < 10, Hb Donors < 5) were selected. The library contains a significant number of Fsp3-rich molecules with limited flexibility (RotBonds < 6) that reflects structural properties of many recently developed NR ligands. Average Fsp3 0.34, average TPSA 77 Å2.

Mol weight LogP

Figure 3. Molecular properties of NR-target library.

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