MOARF: Multi Objective Automated Replacement of … Multi Objective Automated Replacement of...
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in partnership with 28 November 2014 MOARF: Multi Objective Automated Replacement of Fragments Nicholas C. Firth
Transcript of MOARF: Multi Objective Automated Replacement of … Multi Objective Automated Replacement of...
in partnership with
28 November 2014
MOARF: Multi Objective Automated Replacement of Fragments
Nicholas C. Firth
Outline
• Introduction
• MultiObjective Automated Replacement of Fragments (MOARF)
• Prospective validation
• Application to drug discovery efforts
• Summary
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Multiobjective Optimisation• One of the main pitfalls in drug discovery is that preclinical development
candidates often maintain features of the hits from which they are derived
• Optimising in multiple objectives simultaneously often leads into synthetically challenging chemical space that teams are more reluctant to explore
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Fragment Based de novo Design
Synthetically Tractable Exploration of Chemical Space
• de novo design is used to efficiently explore chemistry space and provide synthetically feasible design ideas
• We have chosen to use a fragment based approach to balance synthetic tractability and exploration of chemical space
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Hypothesis
de novo design + multiobjective evaluation
≈ progress to chemical series
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Outline
• Introduction
• MultiObjective Automated Replacement of Fragments (MOARF)
• Prospective validation
• Application to drug discovery efforts
• Summary
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MultiObjective Automated Replacement of Fragments• MOARF takes an input set of molecules (or a
single molecule)
• It then breaks the molecule into fragments
• For each fragment in the molecule a set of replacements is identified
• New molecules are then constructed by changing one fragment from the original
• These are then filtered
• Finally these molecules are scored
• If the stop condition is not met then the top scoring molecules go through this process again
Read Parameter
File
Is MoleculeFragmented?
Fragment Molecule
IdentifyReplacements
Construct New Molecules
FilterMolecules
ScoreMolecules
Is Stop Condition Satisfied?
WriteOutput
File
No
Yes
Yes
No
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An Abstract Example 7
An Abstract Example
✔ ✗✔
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How Does MOARF Compare?
• Other fragment replacement de novo design methods exist• Skeleton fragments1
• Pre-categorised fragments2
• To avoid any potential pitfalls of these methods MOARF uses a different approach
SubstitutionLinker Ring
Step 1: Identify a replacement
Step 2: Identify a substitution pattern
1. N. P. Todorov; P. M. Dean, Evaluation of a method for controlling molecular scaffold diversity in de novo ligand design. J. Comput. Aided Mol. Des., 1997,11(2), 175-192.
2. K. Kawai; N. Nagata; Y. Takahashi, De Novo Design of Drug-Like Molecules by a Fragment-Based Molecular Evolutionary Approach. J. Chem. Inf. Model., 2014, 54(1), 49-56.
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02468
1012
10 100 10,000 130,000
Fragmenter and Database
Synthesised organic molecules (>8m)
Cut molecules into unique fragments
(~0.8m)
Filtered fragment database (~170k)
No. Fragments in ‘Database’
log(
Siz
e of
Che
mic
al S
pace
)
170,000
IADE ??
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Database Snapshot
Fragment Count Fragment1 Count1 Fragment2 Count2 Fragment3 Count3
520,125 496,623 14,825 5,368
• Frequency, location of cutpoints and some calculated properties are retained in the fragment database
• Frequencies of fragments and substitution patterns can be used to guide decisions
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5,7,7
Rapid Alignment of Topological Scaffolds - Alignment
• To make it efficient MOARF has to be able to give not just suitable replacements but also suitable alignments
Replacements
• A mapping of the environment around a substitution point, Rapid Alignment of Topological Scaffolds (RATS), was developed to get round this problem
Substitution Point 4,7,7 Hydrogen Bond Donor
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Rapid Alignment of Topological Scaffolds - Alignment
5,7,7 4,7,75,6,7 1,6,7
5,7,7 4,7,7
6,7,7 2,5,7
• To make it efficient MOARF has to be able to give not just suitable replacements but also suitable alignments
• A mapping of the environment around a substitution point, Rapid Alignment of Topological Scaffolds (RATS), was developed to get round this problem
Replacements
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Outline
• Introduction
• MultiObjective Automated Replacement of Fragments (MOARF)
• Prospective validation
• Application to drug discovery efforts
• Summary
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CDK2 - Defining an OptimisationProblem• To validate MOARF a multiobjective medicinal chemistry
optimisation problem was chosen
• Chose to use an in-house project which focused on minimising the rate of metabolism of a CDK2 inhibitor whilst maintaining the activity against CDK2
Hypothesis
SeliciclibWilson, S. C.; Atrash, B.; Barlow, C.; Eccles, S.; Fischer, P. M.; Hayes, A.; Kelland, L.; Jackson, W.; Jarman, M.; Mirza, A.; Moreno, J.; Nutley, B. P.; Raynaud, F. I.; Sheldrake, P.; Walton, M.; Westwood, R.; Whittaker, S.; Workman, P.; McDonald, E. Design, synthesis and biological evaluation of 6- pyridylmethylaminopurines as CDK inhibitors. Bioorg. Med. Chem. 2011, 19, 6949-6965
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CDK2 - Scoring
• A previous computational validation showed us that 3D similarity and 2D similarity incorporated in the scoring function produced feasible designs
• A local QSAR model was also introduced into the multiobjective scoring function
3D Similarity 2D Similarity QSAR Model ClogP
• These scores were then fused using a weight sum of Z scores1
1. Sastry, G. Madhavi, VS Sandeep Inakollu, and Woody Sherman. "Boosting virtual screening enrichments with data fusion: Coalescing hits from 2D fingerprints, shape, and docking." J. Chem. Inf. 2013.
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CDK2 - Optimisation
One Molecule
Two fragments
Ten replacements
Score using consensus model
Keep top 25
20 Molecules
20 Molecules
400 Molecules
25 Molecules
500 Molecules
100 Cycles
~17k
~12k
>213m ~43k ~310
MOARF
9k
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CDK2 - Synthesis and Testing
• Fourteen of the final ‘top 25’ compounds were synthesised• Picked according to relative ease of synthesis
• All these compounds have been tested in an ATP competitive assay measuring activity against CDK2• n = 3
• They have also been tested in a Human Liver Microsome turnover assay• n = 3
Inactive High rate of metabolism
FourteenMOARF
DesignedCompounds
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CDK2 - Results
26 93
Generation Number
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CDK2 - Results
26 93
Generation Number
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CDK2 - Results
26 93
Generation Number
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CDK2 - Results
26 93
Generation Number
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CDK2 - Results
26 93
Generation Number
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Outline
• Introduction
• MultiObjective Automated Replacement of Fragments (MOARF)
• Prospective validation
• Application to drug discovery efforts
• Summary
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KDM4
• Targeting the epigenetic KDM4 subfamily of proteins is an active drug discovery project at The ICR in collaboration with The SGC and The University of Newcastle
• An initial hitting finding campaign, including an HTS, resulted in two prioritisedchemical series
Good cell permeability
Moderateactivity
Poor cell permeability
Good activity
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Core
KDM4 - Median Molecules
• The first set of experiments run were Median Molecules1 experiments, to explore the chemical space between these two molecules
Ideal compound?
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1. Brown et al. ‘A graph-based genetic algorithm and its application to the multiobjective evolution of median molecules’ J. Chem. Inf. Comp. Sci. 2004
Core
KDM4 – Median Molecules Design 27
Core
KDM4 – Structure-based Design• As the project progressed, in-house protein crystallography led to high
resolution structures for both KDM4A and KDM4B
• These structures were used to create an AutoDock-based scoring function
• The core structure was used as a static fragment with two dynamic methylsattached
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Core
KDM4 – Structure-based Design• After ~70 iterations the top ranked compounds had a common optimal
pharmacophore, so MOARF was terminated
• This pharmacophore is distinct from molecules currently being synthesised
• Optimised molecules are predicted to satisfy multiple key protein interactions that the team had independently identified as potentially important
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CoreCore
Summary
• Designed and implemented an integrated and adaptable workflow for the multiobjective optimisation of drug-like molecules
• Performed an experimental validation of MOARF
• Started from a fragment of interested
• Optimised to drug-like molecules
• Molecules shown to be active and with improved HLM turnover
• Applied MOARF to an ongoing drug discovery project
• Used a structure-based scoring method
• Optimised to drug-like molecules
• Molecules predicted to make key interactions of interest
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Acknowledgements
Supervisors• Julian Blagg• Nathan Brown
in silico Med Chem• Yi Mok• Michael Carter• Joshua Meyers• Fabio Broccatelli• Lewis Vidler• Sarah Langdon
Med Chem 1• Butrus Atrash
HDSD• Kathy Boxall• Yvette Newbatt• Mark Stubbs• Lisa O’Fee• Rosemary Burke
DMPK• Jennie Roberts• Angela Hayes
ETH-Zurich• Daniel Reker• Gisbert Schneider
The RDKitters
Funding
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Fragments - SynDiR
• When performing any replacement of fragments there are two key questions to address• Is this a good replacement?• Can we make this molecule?
• Whether a replacement is good is dependant on the design criteria, so we just need a big database to search from
• Whether we can make a molecule comes down to two points• Can we make the fragment?• Can we make the fragment in the context of this molecule?
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