“Making LeadDiscoveyless Complex?” Mike Hann, Andrew Leach & Gavin Harper. Gunnels Wood Rd...
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Transcript of “Making LeadDiscoveyless Complex?” Mike Hann, Andrew Leach & Gavin Harper. Gunnels Wood Rd...
“Making Lead Discovey less Complex?”
Mike Hann, Andrew Leach & Gavin Harper.
Gunnels Wood RdStevenageSG1 2NY
email [email protected]
Discovery Research
GlaxoSmithKline Medicines Research Centre
Introduction
A simple model of molecular recognition and it’s implications
Experimental data
An extreme example
Conclusions
HTS & Libraries - have they been successful at revolutionising the drug discovery business? Despite some successes, it is clear that the high throughput
synthesis of libraries and the resulting HTS screening paradigms have not delivered the results that were initially anticipated.
Why?
– immaturity of the technology,
– lack of understanding of what the right types of molecule to make actually are . (design problem)
– the inability to make the right types of molecules with the technology . (synthesis problem)
The Right Type of Molecules?
Drug likeness
– Lipinski for oral absorption
– Models (eg Mike Abrahams) for BBB penetration
– But all these address the properties required for the final candidate drug
Lead Likeness
– What should we be seeking as good molecules as starting points for drug discovery programs?
– A theoretical analysis of why they need to be different to drug like molecules
– Some practical data
A very simple model of Molecular Recognition
Define a linear pattern of +’s and -’s to represent the recognition features of a binding site
– these are generic descriptors of recognition (shape, charge, etc)
Vary the Length (= Complexity) of this linear Binding site as +’s and -’s
Vary the Length (= Complexity) of this linear Ligand up to that of the Binding site
Calculate probabilities of number of matches as ligand complexity varies.
Example for binding site of 12 features and ligand of 4 features:
Feature Position 1 2 3 4 5 6 7 8 9 10 11 12Binding site features - - + - + - - + - + + +
Ligand mode 1 + + - +
Ligand mode 2 + + - +
Probabilities of ligands of varying complexity (i.e. number of features) matching a binding site of complexity 12
0
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2 3 4 5 6 7 8 9 10 11 12Complexity of Ligand (I.e. number of ligand features)
Pro
bab
ilit
y
Match any1 matches2 matches3 matches4 matches5 matches6 matches7 matches8 matches 9 matches10 matches11 matches
As the ligand/receptor match becomes more complex the probability of anygiven molecule matching falls to zero. i.e. there are many more ways of getting it wrong than right!
Example from last slide
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Ligand Complexity
Pro
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ilit
y
Probability of matching just one way
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2 3 4 5 6 7 8 9 10 11 12
Ligand Complexity
Pro
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lity
Probability of measuring binding
Probability of matching just one way
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2 3 4 5 6 7 8 9 10 11 12
Ligand Complexity
Pro
bai
lity
Probability of measuring binding
Probability of matching just one way
Probability of useful event (unique mode)
The effect of potency (binding site 12; ligand complexity </=12)
P (useful event) = P(measure binding) x P(ligand matches)
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Ligand Complexity
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lity
Probability of useful event (unique mode)
Too simple.Low probability of measuring affinity even if there is a unique mode
Too complex.Low probability of finding lead even if it has high affinity
Optimal.But where is itfor any given system?
Limitations of the model Linear representation of complex events
No chance for mismatches - ie harsh model
No flexibility
only + and - considered
But the characteristics of any model will be the same
Real data to support this hypothesis!!
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2 3 4 5 6 7 8 9 10 11 12Ligand Complexity
Pro
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P (useful event) = P(measure binding) x P(ligand matches)
Leads vs Drugs Data taken from W. Sneader’s book “Drug Prototypes and their exploitation”
Converted to Daylight Database and then profiled with ADEPT
480 drug case histories in the following plots
Sneader Lead Sneader Drug WDI
Leads are less complex than drugs!!
-300
-200
-100
0
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300
400
0 100 200 300 400 500 600 700 800
MW of Sneader Drugs
Ch
an
ge i
n M
W i
n g
oin
g f
ro
m
Sn
ea
der L
ea
der t
o D
ru
gs
Change in MW on going from Lead to Drug for 470 drugs
Average MW increase = 42
ADEPT plots for WDI & a variety of GW libraries
Molecules in libraries are still even more complex than WDI drugs, let alone Sneader Leads
WDI
WDI
WDIWDI
WDI
WDI
Library compounds are often far too complex to be found as leads !!
In terms of numbers
Astra Zeneca data similar using hand picked data from literature
AZ increases typically even larger
RSC/SCI Medchem conference Cambridge 2001. MW increase ca. 70-90 depending on starting definitions
Average property values for the Sneader lead set, average changeon going to Sneader drug set and percentage change.
Av #arom
arom
% AvClogP
ClogP
% AvCMR
CMR
%
1.3 0.2** 15 1.9 0.5** 26 7.6 1.0** 14.5
Av # HBA
HBA
% Av #HBD
HBD
% Av #heavy
heavy
%
2.2 .3** 14 .85 -.05+ (4) 19. 3.0** 16
AvMW
MW
% AvMV
MV
% Av #Rot B
Rot B
%
272 42.0** 15 289 38.0** 13 3.5 .9** 23
Catch 22 problem
We are dealing with probabilities so increasing the number of samples assayed will increase the number of hits (=HTS).
We have been increasing the number of samples by making big libraries (=combichem)
And to make big libraries you have to have many points of diversity
Which leads to greater complexity
Which decreases the probability of a given molecule being a hit
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2 3 4 5 6 7 8 9 10 11 12Ligand Complexity
Pro
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Concentration as the escape route
Screen less complex molecules to find more hits
– Less potent but higher chance of getting on to the success landscape
– Opportunity for medicinal chemists to then optimise by adding back complexity and properties
Need for it to be appropriate assay and ligands
– e.g the extreme Mulbits (Multiple Bits) approach
– Mulbits are molecules of MW < 150 and highly soluble.
– Screen at up to 1mM
An example indicating how far this can be taken
– from 5 years ago - Thrombin:
– Screen preselected (in silico) basic Mulbits in a Proflavin displacement assay specific
– known to be be specific for P1 pocket.
Catch 21
Thrombin Mulbit to “drug”
NNS
OO
O
N
O
NN
NH2
H
H
Thrombin IC50 = 4µM (15 min pre-incubation; for assay conditions see reference 23)
NHN
NH2
2-Amino Imidazole (5mM), as thesulphate, showed 30% displacementof Proflavin (18µM) from Thrombin (10µM)
(cf Benzamidine (at 5mM) shows 70% displacement) undersimilar conditions
Absorbance at 466nM relative to that at 444nM was used as the measure of amount of proflavin displaced
Related Literature examples of Mulbits type methods
Needles method in use at Roche .Boehm, H-J.; et al Novel Inhibitors of DNA Gyrase: 3D Structure
Based Biased Needle Screening, Hit Validation by Biophysical Methods, and 3D Guided Optimization. A Promising Alternative to Random Screening. J. Med. Chem., 2000, 43 (14), 2664 -2674.
NMR by SAR method in use at Abbott Hajduk, P. J.; Meadows, R. P.; Fesik, S. W.. Discovering high-affinity
ligands for proteins. Science, 1997, 278(5337), 497-499. Ellman method at Sunesis
Maly, D. J.; Choong, I. C.; Ellman, J. A.. Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors. Proc. Natl. Acad. Sci. U. S. A., 2000, 97(6), 2419-2424.
Enzyme target - bangs per bucks
-5
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-2
-1
0
1
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3
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750
MW of inhibitor
Lo
g E
nzy
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hib
itio
n
Interesting monomer
Most interesting lead
Plot of Log Enzyme activity vs MW for “Interesting monomer” containing inhibitors
MWM
nM
H2L problems ?
Lipinski Data zone
Lead Continuum
350 Mwt >500 Mwt <200
Drug-likeLeadlike
HTS screeningNon-HTS
Shapes (Vertex )Needles(Roche)MULBITS(GSK)Crystallead(Abbott)SARbyNMR(Abbott)
Slide adapted from Andy Davis @ AZ
In conclusion
Lipinski etc does not go far enough in directing us to leads.
We have provided a model which explains why. “Everything should be made as simple as
possible but no simpler.” Einstein
– Simple is a relative not absolute term where is that optimal peak in the plot for each target?
– Simple does not mean easy!!
Thanks to:Andrew Leach, Gavin Harper. Darren Green, Craig Jamieson, Rich Green, Giampa Bravi, Andy Brewster, Robin Carr, Miles Congreve,Brian Evans, Albert Jaxa-Chamiec, Duncan Judd, Xiao Lewell, Mika Lindvall, Steve McKeown, Adrian Pipe, Nigel Ramsden, Derek Reynolds, Barry Ross, Nigel Watson, Steve Watson, Malcolm Weir, John Bradshaw, Colin Grey, Vipal Patel, Sue Bethell, Charlie Nichols, Chun-wa Chun and Terry Haley.Andy Davis and Tudor Oprea at AZ
Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery
Michael M. Hann,* Andrew R. Leach, and Gavin Harper
J. Chem. Inf. Comput. Sci., 41 (3), 856 -864, 2001.
Is There a Difference between Leads and Drugs? A Historical Perspective
Tudor I. Oprea,* Andrew M. Davis, Simon J. Teague, and Paul D. Leeson J. Chem. Inf. Comput. Sci., ASAP Articles