New Dedicated Design of Compound Library for Fragment-based … · 2019. 11. 25. · T o t o p to top next previous References 1. Boyd S. M., de Kloe G. E. Fragment library design:

Dedicated Design of

Compound Library for

Fragment-based Drug Discovery

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Dedicated Design of Compound Library for FBDD

• Specially designed and synthesized for FBDD

• High novelty of chemical structures

diversity analysis to eMolecules and most common vendors databases

• Diversification of the Library includes:

Linear fingerprint, pharmacophore and 3D analysis

• High Quality of the molecules: rigorous Phys-Chem parameters,

PAINS & in-house developed structure filters

• Rapid SAR generation potential

Short term molecules selection and synthesis for follow-up testing analogues

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1,139 Building Blocks

carefully selected novel Fsp3-enriched molecules

+

1,246 Decorating reagents

pharmacologically privileged and selected by Phys-Chem parameters

structures

463,000 compounds

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1st Step. Virtual coupling

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2nd Step.

“Rule of three”-like restrictions:

• 150 < MW < 300

• –2 < ClogP < 3

• HDon ≤ 3

• HAcc ≤ 4

• RotB ≤ 3

Other requirements

• TPSA ≤ 70 Å2

• clogSw > –3

• Heavy atoms (HAC) ≤ 20

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• PAINS & in-house developed filters for

undesired and reactive functionalities

• At least one ring in structure; no more than

two fused aromatic rings

• No more than one S, Cl, Br; no more than

three F

• Min one additional atom N, O apart from the

main functional group

• No N-arylsulfonamides, no tetrazoles, no

more than 5% of compounds with isolated

benzene ring

Phys-Chem parameters Structural filtering parameters

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3rd Step. Novelty verification

98 % Tanimoto diversity to eMolecules database

62,000 compounds

98 % diversity to Major Competitors Fragment Databases

90 % diversity to Life Chemicals Stock Collection


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4th Step. Complex diversity approach

Tanimoto

diversity

selection 87 %

3D Shape analysis

Pharmacophore

diversity

analysis

Complexity

optimization

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62,000 compounds

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Chemotype control

Possibility of evolution (ideally 2 points)

5th Step. Final set formation

Advanced Set of Tangible Fragments

5,202 compounds

• Synthetic considerations

• Scaffold population analysis

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Phys-Chem properties analysis

0

5

10

15

20

25

0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1

mean Fsp3= 0.58

Maybridge

Ro3 set:

mean Fsp3 = 0.30

% of the cpds

0

5

10

15

10 11 12 13 14 15 16 17 18 19 20

Fsp3

% of the cpds mean HAC = 16.5

HAC


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0

10

20

30

150 200 250 300

% of the cpds mean MW = 232

MW 0

10

20

30

40

50

0 1 2 3 4HAcc

mean HAcc = 2.9 % of the cpds

0

20

40

60

80

0 1 2 3

% of the cpds

mean HDon = 0.3

HDon 0

10

20

30

30 40 50 60 70

% of the cpds

TPSA

mean TPSA = 39 A2 o

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0

20

40

60

-2 -1 0 1 2 3

0

10

20

30

40

50

0 1 2 3

0

5

10

15

20

25

-3 -2,5 -2 -1,5 -1 -0,5 0 0,5 1

mean LogSw = –1.5 % of the cpds

LogSw

% of the cpds mean RotB = 2.0

RotB 0

20

40

60

80

0 1 2 3 4 5

% of the cpds

Ring Count

mean RingCount = 2.5

mean LogP = 1.1 % of the cpds

LogP

10



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Examples of Building Blocks

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Examples of Building Blocks

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Examples of Reagents

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Examples of Fragments

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Examples of already synthesized Fragments over 800 compounds, 100mg+ in stock

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References 1. Boyd S. M., de Kloe G. E. Fragment library design: efficiently hunting drugs in chemical space. Drug

Discovery Today: Technologies 2010, 7, 173–180.

2. Collins I., Jones A. M. Diversity-oriented synthetic strategies applied to cancer chemical biology and

drug discovery. Molecules,2014, 19, 17221–17255.

3. Langdon S. R., Brown N., Blagg J. Scaffold diversity of exemplified medicinal chemistry space. J.

Chem. Inf. Model. 2011, 51, 2174–2185.

4. Joseph-McCarthy D., Campbell A. J., Kern G., Moustakas D. Fragment-based lead discovery and

design. J. Chem. Inf. Model., 2014, 54, 693−704.

5. Koutsoukas A., Paricharak S., Galloway W. R. J. D. et. al. How diverse are diversity assessment

methods? A comparative analysis and benchmarking of molecular descriptor space. J. Chem. Inf. Model.

2014, 54, 230−242.

6. Morley A. D., Pugliese A., Birchall K. et al. Fragment-based hit identification: thinking in 3D. Drug

Discovery Today, 2013, 18, 23–24, 1221–1227.

7. Boyd S. M., Turnbull A. P. , Walse B. Fragment library design considerations. Comput. Mol. Sci., 2012,

2, 868–885.

8. Schulz M. N., Landström J., Bright K., Hubbard R. E. Design of a fragment library that maximally

represents available chemical space. J. Comput. Aided Mol. Des., 2011, 25, 611–620.

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Thank You for Your Kind Attention !

Life Chemicals

Documents

New Dedicated Design of Compound Library for Fragment-based … · 2019. 11. 25. · T o t o p to top next previous References 1. Boyd S. M., de Kloe G. E. Fragment library design: