Evotec AG, 5 th Joint Sheffield Conference on Chemoinformatics, July 2010 Investigation of CDK2 Inhibitor Potency using Electrostatic Potential Complementarity and the Fragment Molecular Orbital Method Creating high-value drug discovery innovation alliances
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Evotec AG, 5 th Joint Sheffield Conference on Chemoinformatics, July 2010 Investigation of CDK2 Inhibitor Potency using Electrostatic Potential Complementarity.
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Evotec AG, 5th Joint Sheffield Conference on Chemoinformatics, July 2010
Investigation of CDK2 Inhibitor Potency using Electrostatic Potential Complementarity and the Fragment Molecular Orbital Method
Creating high-value drug discovery innovation alliances
PAGE 2
Overview
· Molecular Shape and Electrostatic Considerations in Ligand Binding· Case Study: Cyclin-Dependent Kinase 2 (CDK2)
· Understanding Complex Interactions During H2L/F2L/LO· The Fragment Molecular Orbital (FMO) Method· Application of FMO Calculations
PAGE 3
Classical Lock and Key Problem
Ligand “Keys” Receptor “Lock”
· What is required to effectively describe protein::ligand interactions?· Ligand and receptor features to consider:
· Shape· Charge and electrostatic potential· Dynamics
“Everything should be made as simple as possible, but not simpler.” - Einstein
PAGE 4
Scoring Ligand Shape and Electrostatic PotentialTanimoto Coefficient
A B
IA IBOAB
How similar are these?
· Tanimoto coefficient is widely used to compare chemical similarities
· Gaussian Tanimoto compares ligand shapes in 3D
· Electrostatic Tanimoto (TES) is calculated in the similar manner as for Gaussian Tanimoto but an electrostatic field overlap is used instead of volume overlap1
· Implemented in MOE2 and is high throughput (10,000s cmpds)
Tanimoto = 1 = A and B are identical
1) Jennings and Tennant, J. Chem. Inf. Model. 47, 1829-1838, 20072) MOE (The Molecular Operating Environment) http://www.chemcomp.com
PAGE 5
Ligand-Based Shape and Electrostatic Potential Calculations
· Gaussian Tanimoto is a fast shape comparison application, based on the idea that molecules have similar shape if their volumes overlap well and any volume mismatch is a measure of dissimilarity
· Used as a virtual screening tool which can rapidly identify potentially active compounds with a similar shape to a known hit or lead compound
· TES score is sensitive to subtle changes in ligand electrostatics
· Semi-empirical atomic charges using AM1-BCC is recommended 1,2
AM1-BCC is parameterized for good correlation with HF 6-31G* charges 3
2) Jennings and Tennant, J. Chem. Inf. Model. 47, 1829-1838, 2007
3) Balyl, et al., J. Comput. Chem., 132-146, 132, 2000
PAGE 6
1) P. G. Wyatt et al., J. Med. Chem. 51, 4986-4999, 2008
2) M. Congreve et al., J. Med. Chem. 51, 3661-3680, 2008
Case Study: CDK2
· Can ligands be effectively represented and compared using measures of shape and electrostatics?
· Case example taken from the literature.1,2 CDK2 fragment-based screened identified a number of hits. 28 ligands taken from this work were examined.
· Pharmacological inhibitors of cyclin-dependent kinases (CDKs) are currently being evaluated for therapeutic use against cancer and neurodegenerative disorders amongst many other diseases.
Astex AT7519 (CDK2 inhibitor) as an example
PAGE 7
2VU3323130
2VTT2VTQ
27262524
2VTP2VTO
212019
2VTN1716
2VTL2VTI
132VTS2VTR2VTJ
92VTM2VTH2VTA
2VTA
2VTH
2VTM
92VT
J2VT
R2VT
S13
2VTI2VT
L16 17
2VTN
19 20 212VT
O2VT
P24 25 26 27
2VTQ
2VTT
30 31 322VU3
Gaussian Tanimoto
3nM
Fragment Hit Clinical Candidate
AT7519
Hit
GaussianTanimoto
Coefficient
Based on CDK2-Bound Alignment
PAGE 8
0.0
1.
5
4.0
Absolute Difference in pIC50
3nM
AT7519
Fragment Hit Clinical Candidate
Hit
AbsoluteDifference
In pIC50
PAGE 9
2VU3323130
2VTT2VTQ
27262524
2VTP2VTO
212019
2VTN1716
2VTL2VTI
132VTS2VTR2VTJ
92VTM2VTH2VTA
2VTA
2VTH
2VTM
92VT
J2VT
R2VT
S13
2VTI2VT
L16 17
2VTN
19 20 212VT
O2VT
P24 25 26 27
2VTQ
2VTT
30 31 322VU3
Electrostatic Tanimoto - TES
3nM
AT7519
Fragment Hit Clinical Candidate
Hit
ElectrostaticTanimoto
Coefficient
Based on CDK2-Bound Alignment
2VU3 AT7519, 47nM
Case Study: CDK2Optimisation of Shape and Electrostatics
Which interactions are the most important?
What happens when you have a complicated interaction that requires better understanding?
PAGE 101) Chau, P-L., and Dean, P.M., J. Comput.-Aided Mol. Design., 8, 513-525, 1994
Understanding Complex Interactions during H2L/F2L/LO
Multiple equivalent binding modes
Interactions not represented in docking/MM forcefields
“Defragmentation” of large ligands to determine group efficiency
Which interactions are the most important?
What happens when you have a complicated interaction that requires better understanding?
More complex methods required – e.g., free energy and/or quantum mechanical calculations
PAGE 11
PAGE 12
Fragment Molecular Orbital (FMO) Method
Method and throughput
Calculations for systems with 200-300 atoms are routinely ran at Evotec
(~10/day ) using MP2 / 6-31G* , 6-31G(3df,3pd) for Cl and S
PIE (Pair Interaction Energy)
Fragmentation of peptide
Full quantum computation of protein::ligand complexes has been practically impossible until recently due to extremely large resources required for computing
The fragment molecular orbital method1 (FMO) was proposed by K. Kitaura and co-workers– Highly suitable for calculation of large (biological)
systems in parallel computing environment2,3
– Implemented in GAMESS QM suite
– PIEDA4,5 (Pair interaction energy decomposition analysis) provides detailed ligand/protein interaction information
4) Fedorov, D. G., and Kitaura, K., J. Comput. Chem., 28, 222-237, 20075) Nakano et al., Chem. Phys. Lett., 351, 475-480, 2002
1) Kitara et al., Chem. Phys. Lett., 313, 701-706, 1999
2) Komeiji et al., Comput. Biol. Chem., 28, 155-161, 2004
3) Fedorov et al., J. Comput. Chem., 25, 872-880, 2004
The Cl-p Interaction in a Protein::Ligand Complex
Cl- interaction is an attractive interaction, where the major source of attraction is the dispersion force
Calculated interaction energy is 2-3 kcal/mol depending on the chloro species
Optimal distance is ca. 3.6 Å
HF interaction is repulsive
Electron correlation method, such as MP2, needed to probe the interaction accurately
R: universal gas constant ≈ 1.986 cal/KmolT: temperature 310 K
Aim of free energy calculation in a VS campaign is to rank-order moleculessuch that if a selection of high-ranking compounds is obtained and analysed,it is likely that some will show activity.
However, compound activity is likely to span about 5 log orders inmagnitude, which equates to free energy range of around5.5 kcal/mol at 37°C.
1) Williams, D., et al., Angew. Chem. Int. Ed., 43, 6596-6916, 2004
Estimation of Binding Free Energies
Entropy – Enthalpy Compensation
PAGE 28
Estimation of Binding Free Energies
· Relationship between to Ki (IC50) and the free enegy of binding
DG = -RT lnKD
· Free energy of ligand binding consists of two thermodynamic terms
DG = DH – TDS
Basic equations and two thermodynamic terms
• Binding enthalpy Notoriously difficult to optimize due to strict three dimensional requirements
Enthalpic improvement is often not reflected in better affinity, because of the associated
entropy-loss (desolvation)
• Binding entropyDependent primarily on the hydrophobic effect and conformational entropy
Easier to optimize and less affected by compensating enthalpy changes
Key SBDD Concepts
· Entropy-enthalpy compensation phenomenon
· Desolvation penalty (4-8 kcal/mol per polar group)
· Origin of hydrophobic interaction (entropy-driven effect, re-organization of surface water network)
· Two terms contribute to the entropy of binding
Desolvation entropy (always favourable, about 25 cal/mol Å2 for a carbon atom)
Conformational entropy
• Overcoming enthalpy/entropy compensationWell placed H-bond can make a favourable enthalpic contribution of the order of -4 to -5 kcal/mol (1000
– 5000 fold increase in affinity)
Hydrogen bonds should be aimed at already structured regions of the protein
Try achieving multiple H-bonds for flexible residues – positive cooperativity
Be aware of the forced solvent exposure of hydrophobic groups