Electrostatic Similarity
Electrostatic Similarity
Electrostatic Similarity
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<strong>Electrostatic</strong> <strong>Similarity</strong><br />
Anthony Nicholls<br />
Cup VII, Santa Fe, March 7 th 2006
Outline<br />
• Introduction to EON<br />
• EON Joy<br />
• EON Despair<br />
• What EON is and isn’t<br />
• Mutant EONs<br />
• Fast EON. No, really.<br />
• The Meaning of EON
Shape & <strong>Electrostatic</strong>s<br />
m<br />
field<br />
potential<br />
n<br />
field<br />
steric<br />
dv<br />
dv<br />
m<br />
n<br />
=<br />
=<br />
!<br />
=<br />
"<br />
!<br />
=<br />
#<br />
$<br />
$<br />
%<br />
&<br />
%<br />
%<br />
&<br />
&<br />
space<br />
all<br />
2<br />
2<br />
1<br />
2<br />
space<br />
all<br />
2<br />
2<br />
1<br />
2<br />
)<br />
(<br />
)<br />
(<br />
ance<br />
Dist<br />
tic<br />
Electrosta<br />
Shape<br />
/<br />
, =<br />
!<br />
"<br />
ROCS<br />
EON
Shape/<strong>Electrostatic</strong> Tanimoto<br />
Overlap(<br />
A,<br />
B)<br />
Overlap(<br />
A,<br />
A)<br />
+ Overlap(<br />
B,<br />
B)<br />
! Overlap(<br />
A,<br />
B)<br />
• Larger Tanimoto = More similar = Better<br />
• Smaller Tanimoto = Less similar = Worse<br />
• Range= [0,1]<br />
• Value understood, e.g. ST>0.75 = similar shape
<strong>Electrostatic</strong> Tanimoto<br />
ET>0.6
• We Believe Steve<br />
• SAESAR:<br />
– COX2, Dopamine<br />
• Charged Ligands<br />
– PT1B kinase<br />
EON Joy<br />
– Thymidine Synthetase<br />
• BioIsosteres
Schnecke & Boström, 2006<br />
Cilomilast vs. Piclamilast
Steve Muchmore and the How Not to Get Published<br />
ST=0.84<br />
ET=0.56<br />
CT=<br />
HTS<br />
6nM<br />
3M V-HTS<br />
2-Step Synthesis<br />
2nM<br />
ROCS+EON
Shape Tanimoto<br />
0.2 0.4 0.6 0.8<br />
Decoys plus Highly Actives<br />
Shape and <strong>Electrostatic</strong> Tanimoto Similarities to Cox Crystal Ligand<br />
-0.2 0.0 0.2 0.4 0.6<br />
<strong>Electrostatic</strong> Tanimoto<br />
Wombat Decoys<br />
43 highly active<br />
Xray structure Cox2: SC-558
Shape Tanimoto<br />
0.0 0.2 0.4 0.6 0.8 1.0<br />
Dopamine D2 Cluster 1 Centroid vs Highly Actives and Wombat Decoys<br />
3 active structures<br />
ET<br />
Dopamine Active<br />
Wombat Decoys<br />
Centroid<br />
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
Two Thrombin Inhibitors:<br />
Shape Tanimoto 0.51
Two Thrombin Inhibitors:<br />
<strong>Electrostatic</strong> Tanimoto 0.92
BioIsosteres
EON DESPAIR<br />
• Enrichment in Virtual Screening<br />
• Comparing molecules of different charge<br />
• It’s SO slow (That’s why it’s called EON!)
EON Despair
EON Downright Despondent
• A Miracle worker<br />
• Pharmacophores<br />
• “Cressett”<br />
What EON Isn’t
H<br />
Ligand Tautomers/pKa<br />
H<br />
H
Why single structure-EON might fail:2<br />
Ligand 1<br />
Protein
Why single structure-EON might fail:2<br />
Ligand 2<br />
Protein
Potential distribution mismatch<br />
Ligand 1<br />
Ligand 2
Why single structure-EON might fail:3<br />
Suppressed by
Why single structure-EON might fail:3<br />
Suppression<br />
removed
Why single structure-EON might fail:3<br />
Ligand 1<br />
Protein<br />
Suppression<br />
reinforced
Why single structure-EON might fail:4<br />
“mobile hydrogens”- Serine, Tyrosine<br />
H<br />
Ligand 1<br />
Protein
Why single structure-EON might fail:4<br />
H<br />
Ligand 2<br />
Protein
Natural Failures<br />
• Ligand Tautomer/pKa<br />
• Through-space effects<br />
– Alternate interaction sites<br />
• Charge suppression<br />
– Protein pKa variation<br />
• Rotatable protons<br />
– SER, TYR
EON vs. Pharmacophores<br />
• Single pharmacophore model has exactly the same<br />
issues<br />
• Multiple models-<br />
– Weighting of pharmacophores<br />
• Single pharmacophore model<br />
– Partial matches
EON is not Cresset<br />
• Cresset use fields to<br />
find pharmacophores<br />
• Requires very good<br />
charges (QM level)<br />
• Alignment is point<br />
based/ clique detect<br />
• Probably good (and<br />
faster) for screening<br />
• In EON the field is the<br />
pharmacophore<br />
• Seems to work with<br />
force-field level charges<br />
• Alignment is volumebased/<br />
ROCS-based<br />
• Care and attention when<br />
used for screening.<br />
Shape and color the<br />
appropriate comparison
Multiple Shape Models<br />
Shape Set 1<br />
Shape Set 3<br />
Shape Set 2
Multiple Shape and <strong>Electrostatic</strong><br />
Shape Set 1<br />
Models<br />
Shape & Electro Set 1<br />
Shape & Electro Set 2<br />
Shape & Electro Set 3
Example of Good EON
EON: Database searching, DHFR<br />
• Pre-screen w/ROCS<br />
– S.T. > 0.75<br />
– 8100 -> 315 hits<br />
• Rank by E.T.
2dsim = 0.58<br />
Great Lead Hop<br />
Rank(ST) = 173/315<br />
Rank(ET) = 34/315
EON Happiness<br />
• First find good shapes<br />
• Rerank within good shapes<br />
• Pareto ranking/ harmonic averaging<br />
• Don’t expect great ‘enrichment’<br />
– <strong>Electrostatic</strong> information degrades rapidly with shape<br />
mismatch
Charged Molecules & EON<br />
• The overlap of monopole fields is not formally<br />
convergent!<br />
• Distant Monopoles dominate Local Dipoles
Convergence<br />
[ ]<br />
!<br />
"<br />
"<br />
"<br />
"<br />
#<br />
#<br />
#<br />
###<br />
###<br />
dr<br />
dr<br />
r<br />
r<br />
r<br />
then<br />
r<br />
r<br />
if<br />
dr<br />
r<br />
r<br />
r<br />
d<br />
drd<br />
r<br />
r<br />
r<br />
dxdydz<br />
r<br />
r<br />
2<br />
2<br />
1<br />
2<br />
,<br />
1<br />
2<br />
2<br />
1<br />
2<br />
2<br />
1<br />
2<br />
1<br />
)<br />
(<br />
)<br />
(<br />
1<br />
)<br />
(<br />
)<br />
(<br />
)<br />
(<br />
)<br />
sin(<br />
)<br />
(<br />
)<br />
(<br />
)<br />
(<br />
)<br />
(<br />
$<br />
$<br />
$<br />
$<br />
$<br />
%<br />
&<br />
&<br />
$<br />
$<br />
$<br />
$<br />
L<br />
K<br />
1<br />
/<br />
0<br />
)<br />
,<br />
(<br />
)<br />
,<br />
(<br />
)<br />
,<br />
(<br />
)<br />
,<br />
(<br />
!<br />
"<br />
+ B<br />
A<br />
Overlap<br />
B<br />
B<br />
Overlap<br />
A<br />
A<br />
Overlap<br />
B<br />
A<br />
Overlap
Solvent Boundary Effect:<br />
Charge-Charged, Charged-Neutral, Neutral-Neutral<br />
1<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
0<br />
5 10 15 20 25 30<br />
crg-crg1<br />
crg-crg2<br />
crg-neu1<br />
crg-neu2<br />
neu-neu1<br />
neu-neu2
Neutral<br />
Thermolysin Inhibitors<br />
Charged
ET(-2)<br />
0.52<br />
0.53<br />
0.54<br />
0.02<br />
0.01<br />
-0.26<br />
0.03<br />
Thermolysin Ligands: H 2 0<br />
ET(-1)<br />
0.64<br />
0.54<br />
0.76<br />
0.11<br />
0.06<br />
-0.30<br />
0.10
650 <strong>Electrostatic</strong> Tanimotos:<br />
Charged Target, Charged + Neutral Queries<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1<br />
-0.2<br />
Uncharged<br />
Mind The Gap!<br />
Charged
Potential Improvements<br />
• Scaled Tanimotos<br />
• Vector (E) Tanimoto<br />
• “You could say the magic ingredient is..”<br />
– (Marge Simpson, “The Simpsons: Lisa the Vegetarian”,<br />
15 th October, 1995)
Scaled Tanimoto
650 Scaled <strong>Electrostatic</strong> Tanimotos:<br />
Charged Target, Charged + Neutral Queries<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2<br />
y = 2.4025x + 0.0026<br />
R 2 = 0.9808<br />
y = 1.0005x - 0.0001<br />
R 2 = 1<br />
-0.2 0 0.2 0.4 0.6 0.8 1
650 Scaled <strong>Electrostatic</strong> Tanimotos:<br />
Neutral Target, Charged + Neutral Queries<br />
Scaled <strong>Electrostatic</strong> Tanimoto<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2<br />
Charged<br />
Unscaled <strong>Electrostatic</strong> Tanimoto
Vector Field Tanimotos<br />
• Monopoles die off as 1/r 2 , (Dipoles as 1/r 3 )<br />
– Don’t dominate long range<br />
– Formally convergent overlap functions<br />
• More variation between molecules<br />
– Lower Tanimotos
0.35<br />
0.3<br />
0.25<br />
0.2<br />
0.15<br />
0.1<br />
0.05<br />
-0.05<br />
-0.1<br />
-0.15<br />
-0.2<br />
Solvent Boundary Effect:<br />
Vector Field Tanimoto<br />
0<br />
0 5 10 15 20 25 30 35<br />
crg-crg1<br />
crg-crg2<br />
crg-neu1<br />
crg-neu2<br />
neu-neu1<br />
neu-neu2
650 Field <strong>Electrostatic</strong> Tanimotos:<br />
Charged Target, Charged + Neutral Queries<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2<br />
Uncharged<br />
Charged
650 Field <strong>Electrostatic</strong> Tanimotos:<br />
Neutral Target, Charged + Neutral Queries<br />
Field Tanimoto<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2<br />
y = 0.4139x + 0.029<br />
R 2 = 0.8629<br />
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1<br />
Potential Tanimoto
The extra ingredient is..<br />
• The ‘B’ in ‘PB’<br />
..Salt!<br />
• Models mobile ions as a continuum<br />
• Linear & Non-Linear versions<br />
• Mimic mobile charges in active sites?
650 <strong>Electrostatic</strong> Tanimotos+80mM Salt:<br />
Neutral Target, Charged + Neutral Queries<br />
Salted <strong>Electrostatic</strong> Tanimoto<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2<br />
y = 0.6302x + 0.0241<br />
R 2 = 0.9477<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
<strong>Electrostatic</strong> Tanimoto
650 <strong>Electrostatic</strong> Tanimotos+80mM Salt:<br />
Charged Target, Charged + Neutral Queries<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2
650 Salt <strong>Electrostatic</strong> Tanimotos<br />
Charged Target, Charged + Neutral Queries<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2<br />
40mM<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2<br />
80mM<br />
1<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
-0.2 0 0.2 0.4 0.6 0.8 1<br />
-0.2<br />
120mM
Effects of Salt on Potentials:<br />
Differential Charge Placement, +1/-1 kT contours<br />
Formal<br />
charge<br />
No<br />
Salt<br />
ET=0.68<br />
0.04mM 30mM 0.08mM<br />
90mM<br />
ET=0.29 ET=0.22<br />
ET=0.029 ET=0.05
ET(-2)<br />
0.17<br />
0.16<br />
0.21<br />
0.14<br />
0.08<br />
-0.15<br />
0.13<br />
Thermolysin Ligands: Brine<br />
ET(-1)<br />
0.15<br />
0.02<br />
0.32<br />
0.32<br />
0.18<br />
-0.18<br />
0.26
Schnecke & Boström, 2006<br />
Cilomilast vs. Piclamilast
Saving Boström!<br />
ET=0.02<br />
ET=0.11
Are Active Sites Salty?<br />
• Dielectrics are about reorientation of<br />
dipoles<br />
• Ionic environments are about the migration<br />
of charges, e.g. protons.<br />
• I.e. maybe we are supposed to be using salt<br />
in EON comparisons!
EON: definition<br />
Conclusions<br />
1. An immeasurably long period of time<br />
2. A divine power or nature emanating from the<br />
Supreme Being and playing various roles in<br />
the operation of the universe