Compound collection enchancement strategy

Июль 27, 2022

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Compound collection enchancement strategy

Содержание

2. Key steps of HTS library design I. Design of scaffold library II. Reshaping of the reagent
3. I. Design of scaffold library Scaffold selection is a CRUCIAL step in design of HTS library.
4. I. Design of scaffold library Scaffold should contain 2–4 (preferably 2–3) rings and 1–2 ring systems
5. I. Design of scaffold library Scaffold should represent an attractive chemotype No bad groups, reactive groups,
6. I. Design of scaffold library Scaffold should not be represented in superior set of LC stock
7. I. Enumeration of scaffold BBs At least four variations are proposed for the scaffold’s weak DPs
8. II. Reagent database A database of at least ~800–1000 appropriate reagents is needed for such a
9. IV. Filtering by PhysChem / Structure All available filters for bad, PAINS, reactive etc. (should not
10. V. Filtering by Novelty 98% Tanimoto diversity to competitors (E-molecules). 95% Tanimoto diversity to Advanced HTS
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Слайд 2

Key steps of HTS library design
I. Design of scaffold library
II.

Reshaping of the reagent library

IV. Two-phase diversity selection

IV. Filtering by physico-chemical/structural parameters

V. Checking for the sufficient novelty

III. Virtual coupling

VI. Control of Fsp3 and abundant chemotypes

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I. Design of scaffold library
Scaffold selection is a CRUCIAL step in

design of HTS library.
For a year program, ~200 scaffolds are selected (can be done in parts) – mostly proposed by chemists
A chemoinformatic definition of scaffold should be used (i.e. the scaffold is a combination of core ring systems, linkers combining them, and attachment points). Therefore, different side chains are assigned to the same scaffold.
The scaffold should contain one strong and 1–2 weak diversity points.

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I. Design of scaffold library
Scaffold should contain 2–4 (preferably 2–3) rings

and 1–2 ring systems
Diversity points should be present in every ring system, preferably in every ring. For bi- and polycyclic scaffolds with one ring system, diversity points should be present in at least two different rings, preferably distant ones.

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I. Design of scaffold library
Scaffold should represent an attractive chemotype
No bad

groups, reactive groups, PAINS etc.
No isolated benzene rings (with rare exceptions)
No more than 1 benzene ring (even fused)
No chain amides/sulfamides/ureas/sulfides etc.
HAC < 20 (preferably <=15)
Rotatable bonds <=4 (preferably <=3)
Heteroatom count: 1–6 (preferrably 2–5)
Preferably at least 1 aliphatic and 1 aromatic ring
Approved by MedChem visual expertize

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I. Design of scaffold library
Scaffold should not be represented in superior

set of LC stock (including scaffold-based drug-like compounds only) and opened orders (<=50 cpds)
Scaffold should not be represented in E-molecules (<=50 cpds, <=100 cpds for especially attractive chemotypes – avoid “negative filtering”)
Scaffold should show <85% similarity to existing templates
BBs of scaffold should be prepared in 3–8 steps so that total salary of the BB synthesis per scaffold is 1200-2000 USD

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I. Enumeration of scaffold BBs
At least four variations are proposed for

the scaffold’s weak DPs (preferably 5–6, if it is possible, up to 10 variations can be included, with lower amounts of BBs ordered for synthesis).
Preferable substituent examples: H, Me, i-Pr, CF3, CF3CH2, c-Pr, c-Bu, i-Bu, t-Bu, OH, OMe, CH2OH, SO2Me and F (avoid arylation agents), C(O)NH2, THP, Py and other hetaryls, fused alicyclic rings (for 2 neighbor week DPs) etc. n-Alkyl groups should be avoided; limited use of benzene derivatives is allowed (e.g. fluorine-substituted).
If several types of BBs are possible for the same scaffold (e.g. amine and carboxylic acid), it is preferable to use their different variations.

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II. Reagent database
A database of at least ~800–1000 appropriate reagents is

needed for such a project – at least 400 to start.
The following sets should be considered:
already available reagents (at least 25 g);
purchase from suppliers in China (<3$/g; at least 100 g);
specially designed and synthesized (<10$/g; at least 100 g)
50% arylation / alkylation / epoxides / aldehydes; 20% acylation / sulfonylation / urea synthesis; 30% amines.
No more than 5 reagents derived from the same BMFL scaffold
The following rules should be applied:
Ro2 compliant;
<5% containing isolated benzene;
1–2 rings (except the short list of 10–20 acyclic);
no bad groups / PAINS / reactive (after modification) etc.

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IV. Filtering by PhysChem / Structure
All available filters for bad, PAINS,

reactive etc. (should not give any problems).
Lead-likeness PhysChem parameters:
MW 200…450
cLogP –1…4
HDonors <= 5
Hacceptors <=8
RotatableBonds <=6
Molecular complexity by Wyeth > 20
TPSA < 140
LogS > –6
No too saturated without H-donor
Less than 2 benzenes, <=2 S, <=2 Cl, Br, <=5 F; no chains longer than 6 bonds; at least 2 heteroatoms.
Additional structural filters depending on particular set.

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V. Filtering by Novelty
98% Tanimoto diversity to competitors (E-molecules).
95% Tanimoto diversity

to Advanced HTS collection and opened orders.
Checking for Fsp3 distribution (perfect Fsp3 = 0.6–0.7).
Checking for amide/sulfonamide/urea % (<30%).
<300–400 cpds per scaffold (the rest is removed by Tanimoto).
Check for BMFL scaffold distribution (<=30 compounds)

VI. Chemotype control

VII. Final diversity selection