The Many Roles of Computational Science in Drug
Design and Analysis
Mala L. RadhakrishnanDepartment of Chemistry, Wellesley College
June 17, 2008DOE CSGF Fellows Conference, Washington, D.C.
Amprenavir bound to HIV-1 protease
(HIV)
Kim et al, J. Am . Chem . Soc. 117:1181, 1995
Shafer, Clinical Microbiology Rev., 15:247, 2002
…target rapidly mutates!
Understanding binding specificity and promiscuity
Developing methods for optimal drug cocktail design
Designing broadly-binding HIV-1 protease inhibitors
HIV−1 Protease
Ligand (drug)
Receptor (target)
Goal: create a high-affinity interaction low G
Ligand (drug)
Receptor (target)
“Reality”:
Quantum mechanics
Statistical Mechanics
Model:
Atoms as spheres
Point charges
(Rigid Binding)
Ligand (drug)
Receptor (target)
Model:
Atoms as spheres
Point charges
(Rigid Binding)
+
+
-
-Ligand (drug)
Receptor (target)
+ -
+
+
-
-Drug
Target
+ -
+
+−+
+−++
−
++ −
++
−
++
−
+
+−
++−
++
−
+
+−+ +
−+
+−
+
+ −++
−
Interactions with solvent
+
+
-
-
+ -
Loss of solvation FAVORS LOW CHARGE MAGNITUDES
Drug-target interaction FAVORS HIGH CHARGE MAGNITUDES
+
+ −+
+−
++
−
+ +−
++−
++
−
++
−
++−
+
+
-
-
+ -
Our Model
“solvent continuum”: high dielectric + mobile ions
Designing Toward Multiple Targets
+-
+-
-+
+
-
++
-
?Physical Properties Tailored Recognition
Theoretical Framework
+
L R C
Solvent continuum
Kangas and Tidor, J Chem Phys, 109:7522-7545, 1998
Gbind = vdW + SASA + qLTLqL + qR
TRqR + qRTCqL
G
charge value
The binding profile looks like a paraboloid.
+ …+--
+ +
- -
- +
+ +
- -+
+
--
Theoretical Framework
A promiscuous ligand A specific ligand
Radhakrishnan and Tidor, J. Phys. Chem. B, 111:13419-13435, 2007
Model Systems
Radhakrishnan and Tidor, J. Phys. Chem. B, 111:13419-13435, 2007
• Smaller ligands are more promiscuous than larger ligands
Theory and Model Systems Agree:
Drug charge distribution
Numerical ExperimentTheory
G
qR
Binding profile for a big ligand
Binding profile for a small ligand
black:small red: big
Some Other Insights
• Smaller ligands are more promiscuous
• Hydrophobic ligands are more promiscuous because they are near the center of biological charge space
• Hydrophobic ligands are more promiscuous because they are not as sensitive to shape differences
• Flexibility makes polar and charged ligands more specific, but allows for greater overall binding affinity to multiple partners.
• Asymmetric groups can lead to increased promiscuity
Radhakrishnan and Tidor, J. Phys. Chem. B, 111:13419-13435, 2007
HIV−1 Protease
Understanding binding promiscuity
Developing methods for optimal drug cocktail design
Designing broadly-binding HIV-1 protease inhibitors
Rational Cocktail Design
Drug 2
Drug 1
target variants
decoy
Cocktail Design as an Optimization Problem
Can also combinatorially design individual molecular members simultaneously
Minimize # drugs in cocktail
All targets covered by at least one drug
All targets covered by at least one drug
Minimize sum of binding energies
Size of cocktail is optimal
E
drugs
targ
ets+
de
coy
s
affinity thresholds A
drugs
targ
ets
A’1 0 0 0 1 1 ...
pre-process out decoys
(mxn)
Optimally covering model ensembles
---
-
0 0.5
0.5 -0.5
0 -0.5
0 0Radhakrishnan and Tidor, J. Chem. Inf. Model . 48:1055-1073, 2008
Tiling the Mutation Space
-0.5 0.5
0.5 -0.5
0 -0.5
0 -0.5
0 0.5
0 0.5
0.5 -0.5
-0.5 0.5
q(target,1)
q(t
arg
et,2
)
q(target,1)
q(t
arg
et,2
)
0 0
0 0
HIV−1 Protease
Understanding binding promiscuity
Developing methods for optimal drug cocktail design
Designing broadly-binding HIV-1 protease inhibitors
Designing into Multiple Targets: HIV-protease
Wild Type V82AI84VD30NL90MI50V
L63P, V82T, I84V
Methods:
Molecular “scaffolds”
F
OH
Functional groups
F
Michael Altman et al. J. Amer. Chem Soc., 130: 6099-6113, 2008
G, fast energy function
G,High resolution energy function
Dead-End Elimination, A*:
List of tight-binding compounds
Design of Broadly−Binding HIV−1 Protease Inhibitors
Wild Type
V82AI84VD30NL90MI50V
L63P, V82T, I84V
Physical Properties
0 70
7
Energy threshold (kcal/mol)
Siz
e o
f o
pti
mal
co
ckt
ail
Michael Altman et al. J. Amer. Chem Soc., 130: 6099-6113, 2008
Summary
• Physical Framework for Binding Promiscuity and Specificity
• Methods For Designing Toward Target Ensembles
• HIV-1 Protease as a Case Study
The Many Roles of Computation Computation can…
…map out key interactions in a
binding site.
…design drugs. …predict properties that make drugs
specific or “promiscuous.”
…design drug cocktails.
…model cellular events.
…design novel experimental
systems.
…etc. !
…analyze clinical data
Acknowledgements
MIT Wellesley- Bruce Tidor - Bilin Zhuang and Andrea Johnston- Michael Altman- Dave Czerwinski
- Celia Schiffer, Tariq Rana, Michael Gilson and groups.
Funding: DOE CSGF, NIH, Wellesley College