Electrostatic Similarity

Electrostatic Similarity
Anthony Nicholls
Cup VII, Santa Fe, March 7 th 2006

Outline
• Introduction to EON
• EON Joy
• EON Despair
• What EON is and isn’t
• Mutant EONs
• Fast EON. No, really.
• The Meaning of EON

Shape & Electrostatics
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ROCS
EON

Shape/Electrostatic Tanimoto
Overlap(
A,
B)
Overlap(
A,
A)
+ Overlap(
B,
B)
! Overlap(
A,
B)
• Larger Tanimoto = More similar = Better
• Smaller Tanimoto = Less similar = Worse
• Range= [0,1]
• Value understood, e.g. ST>0.75 = similar shape

Electrostatic Tanimoto
ET>0.6

• We Believe Steve
• SAESAR:
– COX2, Dopamine
• Charged Ligands
– PT1B kinase
EON Joy
– Thymidine Synthetase
• BioIsosteres

Schnecke & Boström, 2006
Cilomilast vs. Piclamilast

Steve Muchmore and the How Not to Get Published
ST=0.84
ET=0.56
CT=
HTS
6nM
3M V-HTS
2-Step Synthesis
2nM
ROCS+EON

Shape Tanimoto
0.2 0.4 0.6 0.8
Decoys plus Highly Actives
Shape and Electrostatic Tanimoto Similarities to Cox Crystal Ligand
-0.2 0.0 0.2 0.4 0.6
Electrostatic Tanimoto
Wombat Decoys
43 highly active
Xray structure Cox2: SC-558

Shape Tanimoto
0.0 0.2 0.4 0.6 0.8 1.0
Dopamine D2 Cluster 1 Centroid vs Highly Actives and Wombat Decoys
3 active structures
ET
Dopamine Active
Wombat Decoys
Centroid
-0.2 0.0 0.2 0.4 0.6 0.8 1.0

Two Thrombin Inhibitors:
Shape Tanimoto 0.51

Two Thrombin Inhibitors:
Electrostatic Tanimoto 0.92

BioIsosteres

EON DESPAIR
• Enrichment in Virtual Screening
• Comparing molecules of different charge
• It’s SO slow (That’s why it’s called EON!)

EON Despair

EON Downright Despondent

• A Miracle worker
• Pharmacophores
• “Cressett”
What EON Isn’t

H
Ligand Tautomers/pKa
H
H

Why single structure-EON might fail:2
Ligand 1
Protein

Why single structure-EON might fail:2
Ligand 2
Protein

Potential distribution mismatch
Ligand 1
Ligand 2

Why single structure-EON might fail:3
Suppressed by

Why single structure-EON might fail:3
Suppression
removed

Why single structure-EON might fail:3
Ligand 1
Protein
Suppression
reinforced

Why single structure-EON might fail:4
“mobile hydrogens”- Serine, Tyrosine
H
Ligand 1
Protein

Why single structure-EON might fail:4
H
Ligand 2
Protein

Natural Failures
• Ligand Tautomer/pKa
• Through-space effects
– Alternate interaction sites
• Charge suppression
– Protein pKa variation
• Rotatable protons
– SER, TYR

EON vs. Pharmacophores
• Single pharmacophore model has exactly the same
issues
• Multiple models-
– Weighting of pharmacophores
• Single pharmacophore model
– Partial matches

EON is not Cresset
• Cresset use fields to
find pharmacophores
• Requires very good
charges (QM level)
• Alignment is point
based/ clique detect
• Probably good (and
faster) for screening
• In EON the field is the
pharmacophore
• Seems to work with
force-field level charges
• Alignment is volumebased/
ROCS-based
• Care and attention when
used for screening.
Shape and color the
appropriate comparison

Multiple Shape Models
Shape Set 1
Shape Set 3
Shape Set 2

Multiple Shape and Electrostatic
Shape Set 1
Models
Shape & Electro Set 1
Shape & Electro Set 2
Shape & Electro Set 3

Example of Good EON

EON: Database searching, DHFR
• Pre-screen w/ROCS
– S.T. > 0.75
– 8100 -> 315 hits
• Rank by E.T.

2dsim = 0.58
Great Lead Hop
Rank(ST) = 173/315
Rank(ET) = 34/315

EON Happiness
• First find good shapes
• Rerank within good shapes
• Pareto ranking/ harmonic averaging
• Don’t expect great ‘enrichment’
– Electrostatic information degrades rapidly with shape
mismatch

Charged Molecules & EON
• The overlap of monopole fields is not formally
convergent!
• Distant Monopoles dominate Local Dipoles

Convergence
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+ B
A
Overlap
B
B
Overlap
A
A
Overlap
B
A
Overlap

Solvent Boundary Effect:
Charge-Charged, Charged-Neutral, Neutral-Neutral
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
5 10 15 20 25 30
crg-crg1
crg-crg2
crg-neu1
crg-neu2
neu-neu1
neu-neu2

Neutral
Thermolysin Inhibitors
Charged

ET(-2)
0.52
0.53
0.54
0.02
0.01
-0.26
0.03
Thermolysin Ligands: H 2 0
ET(-1)
0.64
0.54
0.76
0.11
0.06
-0.30
0.10

650 Electrostatic Tanimotos:
Charged Target, Charged + Neutral Queries
1
0.8
0.6
0.4
0.2
0
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
-0.2
Uncharged
Mind The Gap!
Charged

Potential Improvements
• Scaled Tanimotos
• Vector (E) Tanimoto
• “You could say the magic ingredient is..”
– (Marge Simpson, “The Simpsons: Lisa the Vegetarian”,
15 th October, 1995)

Scaled Tanimoto

650 Scaled Electrostatic Tanimotos:
Charged Target, Charged + Neutral Queries
1
0.8
0.6
0.4
0.2
0
-0.2
y = 2.4025x + 0.0026
R 2 = 0.9808
y = 1.0005x - 0.0001
R 2 = 1
-0.2 0 0.2 0.4 0.6 0.8 1

650 Scaled Electrostatic Tanimotos:
Neutral Target, Charged + Neutral Queries
Scaled Electrostatic Tanimoto
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2
Charged
Unscaled Electrostatic Tanimoto

Vector Field Tanimotos
• Monopoles die off as 1/r 2 , (Dipoles as 1/r 3 )
– Don’t dominate long range
– Formally convergent overlap functions
• More variation between molecules
– Lower Tanimotos

0.35
0.3
0.25
0.2
0.15
0.1
0.05
-0.05
-0.1
-0.15
-0.2
Solvent Boundary Effect:
Vector Field Tanimoto
0
0 5 10 15 20 25 30 35
crg-crg1
crg-crg2
crg-neu1
crg-neu2
neu-neu1
neu-neu2

650 Field Electrostatic Tanimotos:
Charged Target, Charged + Neutral Queries
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2
Uncharged
Charged

650 Field Electrostatic Tanimotos:
Neutral Target, Charged + Neutral Queries
Field Tanimoto
1
0.8
0.6
0.4
0.2
0
-0.2
y = 0.4139x + 0.029
R 2 = 0.8629
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1
Potential Tanimoto

The extra ingredient is..
• The ‘B’ in ‘PB’
..Salt!
• Models mobile ions as a continuum
• Linear & Non-Linear versions
• Mimic mobile charges in active sites?

650 Electrostatic Tanimotos+80mM Salt:
Neutral Target, Charged + Neutral Queries
Salted Electrostatic Tanimoto
1
0.8
0.6
0.4
0.2
0
-0.2
y = 0.6302x + 0.0241
R 2 = 0.9477
-0.2 0 0.2 0.4 0.6 0.8 1
Electrostatic Tanimoto

650 Electrostatic Tanimotos+80mM Salt:
Charged Target, Charged + Neutral Queries
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2

650 Salt Electrostatic Tanimotos
Charged Target, Charged + Neutral Queries
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2
40mM
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2
80mM
1
0.8
0.6
0.4
0.2
0
-0.2 0 0.2 0.4 0.6 0.8 1
-0.2
120mM

Effects of Salt on Potentials:
Differential Charge Placement, +1/-1 kT contours
Formal
charge
No
Salt
ET=0.68
0.04mM 30mM 0.08mM
90mM
ET=0.29 ET=0.22
ET=0.029 ET=0.05

ET(-2)
0.17
0.16
0.21
0.14
0.08
-0.15
0.13
Thermolysin Ligands: Brine
ET(-1)
0.15
0.02
0.32
0.32
0.18
-0.18
0.26

Schnecke & Boström, 2006
Cilomilast vs. Piclamilast

Saving Boström!
ET=0.02
ET=0.11

Are Active Sites Salty?
• Dielectrics are about reorientation of
dipoles
• Ionic environments are about the migration
of charges, e.g. protons.
• I.e. maybe we are supposed to be using salt
in EON comparisons!

EON: definition
Conclusions
1. An immeasurably long period of time
2. A divine power or nature emanating from the
Supreme Being and playing various roles in
the operation of the universe