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					    Computer-Aided Design of Metal Ion Hosts




             Benjamin P. Hay, 30 April 2003

                                U.S. Department of Energy
Battelle                        Pacific Northwest National Laboratory
            The DOE Legacy - Radioactive Waste

50 years of weapons production:                       Bulk of radioactivity
                                                         from metals:
• Uranium Mining, Milling, and Refinement
• Isotope Separation (Enrichment)
                                                                Co-60, Sr-90,
• Fuel and Target Fabrication
                                                                Y-90, Tc-99,
• Reactor Operations
                                                              Sm-131, Cs-137,
• Chemical Separations
                                                              Ba-137, Eu-152,
• Weapons Component Fabrication
                                                              Eu-154, Eu-155,
• Weapons Operations
                                                              Ra-226, Th-230,
• Research, Development, and Testing
                                                               U-233, U-235,
400,000 m3 high-level nuclear waste                            U-238, Pu-238,
220,000 m3 TRU waste                                          Pu-239, Pu-240,
3.3 million m3 low-level nuclear waste                        Pu-241, Am-241,
1.4 billion m3 environmental contamination                        Cm-244



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

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


SOLVENT                                   ION




                   C C
                   C C

                    CC
                    C C
EXTRACTION                                EXCHANGE                               C C C
                                          PROCESS                                 C C C
PROCESS                                                                          C C C




                      C
                                                                                  C C C




                        (1) Initial                                             (1) Initial
C C
CC




                   C C
C C




                   C C
 C C




                    CC
                    C C



                                                 C C C                           C C C
  C




                                                  C C C                           C C C
                                                 C C C                           C C C
                      C



                                                  C C C                           C C C




(2) After mixing   (3) After stripping    (2) After elution                (3) After washing


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

ION SELECTIVE ELECTRODE                PIEZOELECTRIC CRYSTAL
                                             DETECTOR
       V
                                                            




                                                        C CC
                                                       C
       C C C C                                       C       C
        C C C C                                      C       C
       C C C C                                        C     C
                                                        C C




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

      Detoxification                        Chemotherapy - "Magic Bullets"


     O NH OHN HN O
HO                       OH
          HO
 O    N          N       O
                                                                                   M
           O N
                                                                   linker
actinide decorporating agent                                                     chelate
                                             monoclonal
                                              antibody


  Diagnostic Imaging                                O                            O
                                                                                       OH
                                              HO          N       N          N
                                                    O                O          O
                     O               O
                                                        OH          OH         OH
                 HO          N   N   OH             chelate used for Bi-213
                  O          N   N   O
                 HO                  OH

MRI image         Gd contrast agent
                                             Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                                               Hosts for metal ions

                                                     R
    O                     O
                                                                       R
                                                                  HN       O        N       N
HO           N   N        OH               O    NH R
O                          O                                               OH       N
                                                          O       NH                        N
        OH           HO               HO                                                                                O        O
                                                                           OH
                                      HO             HO                                                            O                  O

        O                                            HO
                          O       O                                                N      HN                        O                 O
O            O
                      O               O                                            NH       N                               OO
        O
                              O
                                                                                                                       O          O
                                                         O
             O   O                               O            O                                                         O        O
                                                 O            O                       R O
        O             O                                                              O
                                                         O                        R      R
                                                                                    O R O
             O   O




                                                                                Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
             Computer-Aided Host Design ?

 Identify
candidate         Computational           Host synthesis
structures          screening

                    Molecular
                    modeling           Guest complexation
                    methods

                                    Structural characterization
                                     including X-ray analysis
Design
criteria
                                     Thermodynamic studies,
                                  Binding constant measurement


                                       Test Performance in
                                        actual application



                                       Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Architecture - scaffolds used to connect sets of binding sites

Structure can have a large effect on binding affinity:

    O   O                                         O    O
                     O       O   O                                                    O O
    O   O                                         O   O                          O              O
                         O       O
     O O                     O                     O O                                O O




    1010                 106                       105                                103

and a large effect on selectivity:

            N   N                        N   N

            N   N                        N   N

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



                                                           Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structural effects are often difficult to predict




                               Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
     How do we approach this problem?
                                                    OH2      n+

      O     O                                   O       O
                +   M(OH2)6n+                       M               + 2 H2O
      O     O                                   O       O
                                                    OH2


                                                               n+
      O     O                                   O       O
                    +   Mn+                         M
      O     O                                   O       O




                                            +



            conformational                            metal ion
            reorganization                          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




                              Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Downside - MM models often require parameterization




                               Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Extending MM3 models for f-element complexes




                           Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
What can we learn by examining host structures?




    Li+             Na+                             K+
12-crown-4      15-crown-5                     18-crown-6




                             Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
 Binding site geometry in crowns favors large metals




binding
 form




bound
 form


           Li+            Na+                                  K+


                                Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Size–match is not sufficient for a good fit




                                                     good donor
                                                     orientation




                                                        bad donor
                                                        orientation



                            Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
12-crown-4 versus 14-crown-4




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



² Utot = ² U1 + ² U2




                                                                bound
                                                  ² U2


                               binding
                        ² U1

      free



                                                                complex



                                         Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                        Binding affinity vs. host strain


                       O   O                             16
 O O
O   O                  O   O                     O                1
                        O O                  O       O
 O O                                                     14
                                         O           O
                                                 O

  1                        2                     3       12

                                                         10                        3
                                OO                                         2
               O                         O
           O       O           O                         8                                    5
                                 O                                                 4
          O        O                 O
               O
                                                         6                                          7
               4                     5
                                                                                                6




                                                                    +

                                                                  m
                                                                  N
                                                         K
                                                         o
                                                         g


                                                                  a
                                                                  o
                                                                  p
                                                                  e
                                                                  a
                                                                  o
                                                                  n
                                                                  c


                                                                  x
                                                                  (




                                                                  )
                                                         4




                                                                  t
                                                         l




                                                                  l

                                                                  i
                                                              e
                                                              q
                       O   O
                                                 O
                                                                                                        8
      O O              O   O                 O       O   2
  O
          O             O O                  O       O
  O                                                           0       2        4       6       8      10       12
      O                                          O
                                                                            ² Utot, kcal/mol
      6                    7                     8


                                                         Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                                                      Another example
                        O             O
                                          O
                             O                O
                O       NH       HN       O HN            O
                                                                    -5
   1       HO                                 OH          OH

           HO                                 OH          OH
                                                                   -10
                             R
                                                  R
                                          HN          O
                 O      NH R
2 R=H                                                  OH          -15
            HO                    O       NH
3 R = Me
4 R = Et                     HO                        OH
            HO
                                 HO
                                                                   -20




                                                                               +
                                                                               3

                                                                                   m
                                                                   K

                                                                         F
                                                                   o
                                                                   g


                                                                         e

                                                                                   o
                                                                                   p
                                                                                   e
                                                                                   a
                                                                                   o
                                                                                   n
                                                                                   c


                                                                                   x
                                                                         (




                                                                                   )
                                                                                   t
                                                                   l




                                                                                   l

                                                                                   i
                                                                     e
                                                                     q
                    N             N                N
            O                                             O
                                          O                        -25
       HO                                                     OH              60            70             80            90
  5                                           OH
       HO                                                     OH                       ² Utot, kcal/mol
                                              OH


                                                                    Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                      Actinide sequestering agents
Selective removal of Pu and U from spent fuel is done via solvent extraction:

                  O
             O P O
                                Used at Hanford from 1956 through 1987
                  O
                                Currently used for reprocessing power reactor
                                fuel in France, UK, Japan, and Russia.
  PUREX agent



Agents that also remove Am(III) and Cm(III):
                                                           O        O
         O    O                                       N                  N
              P
     N




TRUEX agent (ANL/Eichrom)                      DIAMEX agent (Numatec)
                                                Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
   A closer look at the malonamide architecture




 optimal                                                    bound form
orientation
                                         2.5
                                       kcal/mol

                     binding form                                   5.5
                                                                  kcal/mol
                3.0
              kcal/mol

  free form


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

             H



     N                 N
Me                         Me
             H
         O         O
                                                                                  X-ray structure of
         trans                       ² Utot = 0.0 kcal/mol                         [Eu(L)2(NO3)3]



             H



     N                 N
Me                         Me
             H
         O         O

             cis                    ² Utot = 0.1 kcal/mol



                                                         Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                    Proof in the pudding . . .


                            Extraction into t-butylbenzene from aqueous solution
N               N           containing 1 M NaNO3, 1.5 mM HNO3, 0.1 mM
    O       O               Eu(N03)3, and 1-µL of 155Eu tracer solution.

                           104
        1
                           102

                                                             1
                           100
                       D
                        E
                        u

                           10-2


                           10-4                                                               2
N               N
    O       O              10-6
                            0.0001        0.001              0.01                  0.1                  1
        2                                         [ligand], mol•lit-1
                                     10 million times more effective


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




          ether          amine                        pyridine N-oxide




        aryl ether               arene                phosphine oxide




          amide       catecholate                                   HOPO




                     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

             Identify
Structure                Computational
            candidate                                      Host synthesis
Generator                  screening
            structures

                           Molecular
                           modeling                    Guest complexation
                           methods

                                                  Structural characterization
                                                   including X-ray analysis
            Design
            criteria
                                                Thermodynamic studies,
                                             Binding constant measurement


                                                        Test Performance in
                                                         actual application



                                         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?

 ether binding sites       Step 1: building                                      Step 2: scoring


                             O        +        O                                     geometry
                                                                                     evaluation
                                 O         O       +   O        O
                                      Li                   Li
                                                                                    strain analysis
                                                       O        O
  Li–O distance – 2.1 Å
                                 +                         Li
                                          O
                                                       O        O                   conformational
                                      O                                             analysis
                             O        Li O
6-coordinate Li+ complex                               O        O
                                                           Li                       QM analysis
                                                       O        O
                             O         O
                                 Li           O        O        O
                                                           Li
                                                       O        O




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




                 +




Objectives:
Build structures by connecting host fragments with linking fragments
• examine all possible connectivities
• examine all conformations for each connectivity
Score structures with respect to how well they complement the guest.
Do it quickly.


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

(1) Define two host fragments       (4) Set dihedral angle on bond




                                    (5) Bond 2nd fragment to link
(2) Choose a potential link




(3) Bond 1st 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   3.42 Å                  4.50 Å                               6.35 Å




6.59 Å   6.84 Å                  6.89 Å                              7.64 Å



         generates 81 structures from methylene
         linkage

8.20 Å   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)

null   Me




                                      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
Validation




             Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
        How did we do?


1   2
                                        rmsd                        ²U
                   host                   (Å)                 (kcal/mol)

                    1                    0.12                      0.23

3   4               2                    0.11                      0.21

                    3                    0.09                      0.10

                    4                    0.08                      0.10

5   6               5                    0.10                      0.08

                    6                    0.11                      0.14




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




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




                              etc . . .




             Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
           Tetradentate ether macrocycles
designed by computer             designed by humans



                       O   O                                       O         O

                       O   O
                                                                   O         O


        0.3 kcal/mol                            7.7 kcal/mol



                                                                         R

                       O   O                                   R                   R
                                                           R        O        O         R
                       O   O
                                                           R        O        O         R
                                                               R                   R

       0.3 kcal/mol                       4.3 to 6.8 kcal/mol

                                Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
                   Applications in progress
Cs, Sr, Ra – ethers, arenes         Actinides -catecholates
Dr. Bruce Moyer, ORNL               Prof. Ken Raymond, UC–Berkeley


+                     +




               +



    Actinides – amides              Actinides - phosphoryl + N-oxides
    Prof. Jim Hutchison, UO         Prof. Robert Paine, UNM



           +           +                                       +



                                     Benjamin P. Hay, Pacific Northwest National Laboratory, 30 April 2003
Structure-function research, scoring                                 HostDesigner
methods, and applications                                            software
PNNL                        ORNL                                      PNNL
Calvin C. Ainsworth         Bruce A. Moyer                            Timothy K. Firman (PD)
Dave A. Dixon                                                         Bert deJong
Dave Feller                 U of Oregon                               John B. Nicholas
Jorge Garza (VS)            James E. Hutchison
                            Timothy J. R. Weakley
Gregg J. Lumetta            Robert D. Gilbertson                      Sponsors
Brian M. Rapko                                                        LDRD program, PNNL and
Jamal Uddin (PD)            UC- Berkeley                              the Office of Chemical
Rubi Vargas (PD)            Kenneth N. Raymond                        Science, Basic Energy
Cungen Zhang (PD)                                                     Sciences, Office of Science
                            U of New Mexico
EMSL - supercomputer        Robert T. Paine

Sponsor
Environmental 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

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


Amides
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.


HostDesigner Software
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.
http://hostdesigner.emsl.pnl.gov


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

				
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