rapid and accessible in silico macrocycle design

Rapid and accessible in silico macrocycle design

Robert A. Scoffin MA, D.Phil, FRSC

BRD4 macrocyclization case study

Macrocyclization

Ligand linking

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3D Molecular Electrostatic

Interaction Potential (MIP) contains

too much information to use

computationally in a reasonable time

Field points provide computationally

tractable framework for electrostatic

similarity

= Positive

= Negative

= Shape

= Hydrophobic


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Background to our case study


> Pyridone-based BRD4 bromodomain

inhibitors with promising anticancer

effects reported by Wang et al.

> Structure-based optimization of

pyridone fragment hit (1) yielded lead

molecule (2) with nM potency

> Macrocyclization (3) further improved

binding affinity, cellular efficacy, and

pharmacokinetic compound properties

Macrocyclization of BRD4 inhibitors

Wang et al. 2017 JMC


> Increased novelty

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Spark

> Scaffold hop using a db of fragments

> Find new R groups from db of available

reagents

> New ideas

> Fragment growing

“The best bioisostere application on the market”


Wizards make experiments easy


Choose the regions in the starter molecule to be joined in the cyclization

Define appropriate attachment points to bias linker design towards existing chemistry

Use 5UEY as excluded volume

Add constraints to sulfonyl and carbonyl negative field points (H-bonds to receptor)

Search ChEMBL Common and Commercial VeryCommon and Common databases

Spark macrocyclization experiment workflow

- 5UEY ligand as starting point for

macrocyclization

PDB 5UEY

Compound 2

Macroyclization








- Keep sp3 hybridized O at attachment point 1

- Allow any atom at attachment point 2

1

2








- 5uey used as excluded volume to guide the

search








- Constrain hydrogen bond acceptor fields that

make H-Bonds with receptor








- Select appropriate search databases and

calculation method


Protocol is adapted to macrocyclization

> Minimization of whole molecule before

second scoring pass

> Maximum number of rotamers are

adapted to macrocyclization experiment


BRD4 macrocycle SAR

> Clear preference for 4-6 atom linkers

Wang et al. 2017 JMC

PDB 5UEX

3 4 5 5 6


X-ray structures of BRD4 inhibitors

PDB 5UEY

Compound 2

PDB 5UEX

Compound 3

> Conserved binding mode with slight conformational rearrangement


Results similar to experimentally validated macrocycles

A1A2

A1A2

Rank 59

5UEX ligand

Score = 0.891

Rank 11

ECFP4 = 0.96

Score = 0.96

Rank 2

ECFP4 = 0.79

Score = 0.921

Rank 9

ECFP4 = 0.80

Score = 0.913

Rank 4

ECFP4 = 0.76

Score = 0.917

Rank 17

ECFP4 = 0.73

Score = 0.904

A1A2

A1A2

A1A2

A1A2

Spark top results contain several linkers that are either identical or very similar to compound 3 (5UEX)

ECFP4 values are Tanimoto similarities to 3

Attachment points A1 and A2 as specified in the method section.


Frequency of different atom linker sizes

Top N

results

3 linker

atoms

4 linker

atoms

5 linker

atoms

6 linker

atoms

7 linker

atoms

10 2 6 1 1 0

25 2 16 4 8 0

50 2 32 12 9 0

> Top Spark results enrich mainly 4 and 5 atom linkers

> 3 atom linkers have lowest incidence

Field points of reference ligand (5UEX) and conformational preferences bias results towards 4-6 atom linker size


Best ranked result for each linker size

Rank 6

3 atom linker

A1A2

Rank 1

4 atom linker

Rank 9

5 atom linker

Rank 2

6 atom linker

A1A2

A1A2A1A2


Results mimic hydrophobic volume of O-ethyl

> Reference binding mode (5UEY)

Rank 1

4 atom

linker

Rank 6

3 atom

linker

> Spark predicts short linkers that mimic

hydrophobic volume of OEt chain

≈ 4 Å distance


> Spark successfully designed macrocycles that are identical or very similar to

reported BRD4 macrocycle inhibitors

> The distribution of generated linker sizes was in good agreement with experimental

SAR data

> The Spark macrocyclization wizard is a quick and easy-to-use workflow to generate

meaningful and diverse design ideas that can guide macrocycle drug discovery

Conclusion

20


Cresset Team

Cresset – 2018 edition


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