Презентация на тему Compound collection enchancement strategy

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

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.

(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.

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

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

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.

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.

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.

(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