Computer-Aided Design of Metal Ion Hosts

Computer-Aided Design of Metal Ion Hosts

Benjamin P. Hay, 30 April 2003

BattelleU.S. Department of EnergyPacific Northwest National Laboratory

The DOE Legacy - Radioactive Waste

50 years of weapons production:

• Uranium Mining, Milling, and Refinement

• Isotope Separation (Enrichment)

• Fuel and Target Fabrication

• Reactor Operations

• Chemical Separations

• Weapons Component Fabrication

• Weapons Operations

• Research, Development, and Testing

400,000 m3 high-level nuclear waste220,000 m3 TRU waste3.3 million m3 low-level nuclear waste1.4 billion m3 environmental contamination

Data from “Linking Legacies”, DOE/EM-0319, January 1997

Bulk of radioactivity from metals:

Co-60, Sr-90,

Y-90, Tc-99,

Sm-131, Cs-137,

Ba-137, Eu-152,

Eu-154, Eu-155,

Ra-226, Th-230,

U-233, U-235,

U-238, Pu-238,

Pu-239, Pu-240,

Pu-241, Am-241,

Cm-244

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Separations

(1) Initial

(2) After mixing (3) After stripping

SOLVENT EXTRACTIONPROCESS

CC

CC

C CCCC

C C

CC

CCC

C C

CC

CC

C CCCC

(1) Initial

(2) After elution (3) After washing

ION

EXCHANGE

PROCESSC C CC C CC C CC C C

C CC C CC C CC C C

C C CC C CC C CC C C

C

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Sensors

ION SELECTIVE ELECTRODE

C C CC C C

V

CC

C C C C

PIEZOELECTRIC CRYSTAL DETECTOR

CCCCC

CC

C CCC

C

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Medical Applications

NH HN

N N

O O

OH

OO

HO

HNO

N

HO

O

Detoxification

actinide decorporating agent

N

N N

NO

HO

O

HO

O

OH

O

OH

Diagnostic Imaging

MRI image Gd contrast agent

NN N

O

HO

OOH

OOH

OOH

OOH

Chemotherapy - "Magic Bullets"

monoclonalantibody

linkerchelate

chelate used for Bi-213

M

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Hosts for metal ions

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

N N

O

OHO

HOO

OH

HO

O

N

N

N

N

NH

NH

HNO

HO

HO

O

O

HO

HO

OH

OH

R

R

R

O O

OO

OO

O

O

O

O

O

O

O

O O

O

O O O O

O O

R

R

R

R

O

O

O

O

O O

O

O

O

O

OO

OO

O

N HN

NH N

Host Design

Computer-Aided ?

Guest complexation

Test Performance in actual application

Host synthesisIdentify

candidatestructures

Design criteria

Structural characterizationincluding X-ray analysis

Thermodynamic studies,Binding constant measurement

Computationalscreening

Molecularmodelingmethods

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Architecture - scaffolds used to connect sets of binding sites

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

N N

N N

N

N

N

N

Hg2+/Cu2+ = 5 Cu2+/Hg2+ = 104

OO

O

O O O

O OO

OOO

OO

OO

OO

OO

OO

OO

1010 106 105 103

Structure can have a large effect on binding affinity:

and a large effect on selectivity:

Structural effects are often difficult to predict

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

How do we approach this problem?

O O

OO

O O

OOM+ Mn+

n+

O O

OO

O O

OOM+ M(OH2)6

n+

n+

OH2

OH2

+ 2 H2O

conformationalreorganization

metal ion complexation

+

free form binding form bound form

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Electronic structure calculations

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Force field calculations are much, much quicker

-40

-30

-20

-40 -30 -20M M k c a l / m o l

QM kcal/mol

0.05 Å

0.17 Å

0.19 Å

MM3 calculations take only 15 seconds/structure on a laptop computer

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Downside - MM models often require parameterization

ether donors

arene donors

High–level electronic structure calculations on simple analogs

Crystal structure data

0.29 Å

0.29 Å

0.25 Å0.23 Å

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Extending MM3 models for f-element complexes

HOPO[U(L)4(SCN)4]

amide

[Gd(L)(OH2)2]

0.19 Å0.14 Å

amine

[Pu(L)2(NO3)2]2+

0.25 Å

pyridine N-oxide

phosphine oxidecarboxylate

[Nd(L)(OH2)3]–

0.17 Å

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

What can we learn by examining host structures?

15-crown-5Na+

18-crown-6K+Li+

12-crown-4

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Binding site geometry in crowns favors large metals

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Na+ K+Li+

bindingform

boundform

Size–match is not sufficient for a good fit

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

good donororientation

bad donororientation

12-crown-4 versus 14-crown-4

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Ligand strain energy

free

binding

bound

² U1

² U2

² Utot = ² U1 + ² U2

complex

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Binding affinity vs. host strain

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12

1

23

4 5

6

7

8

OO

OO

OOO O

OOO

OO

OO

O OO

OOO

OO

O

OOO

O

O

O

OO

O O

O

O

2

OO

O

OO

O

OO

OO

OO

6

4

7 8

1 3

5

² Utot, kcal/mol

l o g K e q ( N a + c o m p l e x a t i o n )

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Another example

-25

-20

-15

-10

-5

60 70 80 905

O

O OO

ONH HN HNO

HO

HO

O O

OH

OH

OH

OH

N N NO

HO

HO

OO

OH

OH

OH

OH

NH

NH

HNO

HO

HO

O

O

HO

HO

OH

OH

R

R

R

1

234

R = HR = MeR = Et

l o g K e q ( F e 3 + c o m p l e x a t i o n )

² Utot, kcal/mol

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Actinide sequestering agents

P

O

OO

O

PUREX agent

Selective removal of Pu and U from spent fuel is done via solvent extraction:

Used at Hanford from 1956 through 1987

Currently used for reprocessing power reactor fuel in France, UK, Japan, and Russia.

P

OO

N

OO

N N

DIAMEX agent (Numatec)TRUEX agent (ANL/Eichrom)

Agents that also remove Am(III) and Cm(III):

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

A closer look at the malonamide architecture

optimal

orientation

free form

binding form

bound form

3.0 kcal/mol

2.5kcal/mol

5.5kcal/mol

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Improved architecture?

NN

OO

MeMe

H

H

NN

OO

MeMe

H

H

² Utot = 0.0 kcal/mol

² Utot = 0.1 kcal/mol

X-ray structure of [Eu(L)2(NO3)3]trans

cis

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Proof in the pudding . . .

10-6

10-4

10-2

100

102

104

0.0001 0.001 0.01 0.1 1

1

2NN

OO

NN

OO

1

2

Extraction into t-butylbenzene from aqueous solution

containing 1 M NaNO3, 1.5 mM HNO3, 0.1 mM

Eu(N03)3, and 1-µL of 155Eu tracer solution.

D E u

[ligand], mol•lit-1

10 million times more effective

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Structural design criteria

ether

amide

aryl ether

catecholate

arene

amine

HOPO

pyridine N-oxide

phosphine oxide

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Structural design is a trial–and–error process

Problem: you have to build structures before you can test them.

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Computer–Aided Host Design

Guest complexation

Test Performance in actual application

Host synthesisIdentify

candidatestructures

Design criteria

Structural characterizationincluding X-ray analysis

Thermodynamic studies,Binding constant measurement

Computationalscreening

Molecularmodelingmethods

StructureGenerator

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Structure-Based Drug Design

Known host structure• steric constraints• H-bond regions• hydrophobic regions

Step 1: Build candidate guests•position functional groups•link with spacer fragments

Step 2: Score the candidates•number of H-bonds•hydrophobic contact area•entropic factors•conformational strain energy

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Structure-based host design?

Li–O distance – 2.1 Å

6-coordinate Li+ complex

OLi

O

OLi

O

O Li

O

O

O

O+

OLi

O O

O

OLi

O O

O

OLi

O O

O

+ OLi

O

ether binding sites

O+O

Step 1: building Step 2: scoring

geometryevaluation

strain analysis

QM analysis

conformationalanalysis

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

HostDesigner Software

+

Objectives:

Score structures with respect to how well they complement the guest.

Build structures by connecting host fragments with linking fragments• examine all possible connectivities • examine all conformations for each connectivity

Do it quickly.

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

LINKER algorithm

(1) Define two host fragments

(2) Choose a potential link

(3) Bond 1st fragment to link

(4) Set dihedral angle on bond

(5) Bond 2nd fragment to link

(6) Set dihedral angle on bond

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Scoring by geometry

0.50 Å 4.50 Å 6.35 Å3.42 Å

6.84 Å 6.89 Å 7.64 Å

8.20 Å

6.59 Å

generates 81 structures from methylene linkage

finds only 9 unique structures rejected

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Linking fragment database

NULL

etc ...

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

CnHm for n = 0 - 6 (excluding alkynes, 3-membered rings, and 4-membered rings)

Menull

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Dimethylated 5– and 6–membered rings

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Selected fused–rings

cis/trans

cis/trans cis/trans

total: 20,094 linking structures

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Example of a LINKER run

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

1 2

3 4

5 6

Input:

Output: 1,242,037 host

structures in 8.0 sec

(MacOS, 800 MHz)

155,255 structures/sec ! ! !

Validation

Are the structures generated by HostDesigner accurate?

optimize- M

optrmsd

Do the structures complement the metal ion?

- M

opt

optimize

² U

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

How did we do?

1 2

3 4

5 6

host

1

2

3

4

5

6

(Å)

0.12

0.11

0.09

0.08

0.10

0.11

(kcal/mol)

0.23

0.21

0.10

0.10

0.08

0.14

² Urmsd

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Second generation

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

1 2

3 4

2 x

Output: 5,802,532 host

structures in 39 sec

(MacOS, 800 MHz)

Input:

OVERLAY algorithm

etc . . .

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Tetradentate ether macrocycles

0.3 kcal/mol

O

OO

O

O

OO

O

designed by computer

0.3 kcal/mol

O

OO

O R

RR

R

RR

R R

4.3 to 6.8 kcal/mol

designed by humans

R

O O

O O

7.7 kcal/mol

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Applications in progressCs, Sr, Ra – ethers, arenes

Dr. Bruce Moyer, ORNL

Actinides – amidesProf. Jim Hutchison, UO

Actinides - phosphoryl + N-oxidesProf. Robert Paine, UNM

Actinides -catecholatesProf. Ken Raymond, UC–Berkeley

++

+

+ +

+

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

HostDesigner software

ORNLBruce A. Moyer

U of OregonJames E. HutchisonTimothy J. R. WeakleyRobert D. Gilbertson

UC- BerkeleyKenneth N. Raymond

U of New MexicoRobert T. Paine

Structure-function research, scoring methods, and applications

PNNLTimothy K. Firman (PD)Bert deJongJohn B. Nicholas

SponsorsLDRD program, PNNL and the Office of Chemical Science, Basic Energy Sciences, Office of Science

PNNLCalvin C. AinsworthDave A. DixonDave FellerJorge Garza (VS)Gregg J. LumettaBrian M. RapkoJamal Uddin (PD)Rubi Vargas (PD)Cungen Zhang (PD)

EMSL - supercomputer

SponsorEnvironmental Management Science Program, Office of Science, Office of Environmental Management, Project Nos. 54679, 55087, 64974, 73759, 82773

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Further information

Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003

Hay, B. P.; Firman, T.K. “HostDesigner: A Program for the de Novo Structure-Based Design of Molecular Receptors with Binding Sites that Complement Metal Ion Guests.” Inorg. Chem. 2002, 41, 5502.

HostDesigner Software

http://hostdesigner.emsl.pnl.gov

Hay, B. P.; Hancock, R. D. Coord. Chem. Rev. 2001, 212, 61.

Lumetta, G. J.; Rapko, B. M.; Garza, P. A.; Hay, B. P.; Gilbertson, R. D.; Weakley, T. J. R.; Hutchison, J. E. J. Am. Chem. Soc., Comm. Ed. 2002, 124, 5644.

Amides

Ethers