Development of new force field

Molecular force fields development is required human time and expertise.  Comp Chemists often uses FF for their task.  So force field is key parameter to conduct calculations.  But it has still room for improvement.
I have not know that major FF, AMBER-family does not have access to bond order information.

Recently I read an article for new FF development. The title is ‘Open Force Field Consortium: Escaping atom types using direct chemical perception with SMIRNOFF v0.1’
https://www.biorxiv.org/content/early/2018/07/13/286542.full.pdf+html

Fig1 in this article shows representative geometries of 1,2,3,4-tetraphenylbenzene. The geometries are quite different in different Force Fields.

The author proposed new approach called ‘direct chemical perception’ instead of atom typing.
This approach is based on SMIRKS patterns and named SMIRKS Native Open Force
Field (SMIRNOFF) format.
This new FF is now implemented via OpenMM and the Open Eye tools. And good news! The author has plan to implement the FF in RDKit.

If reader who can use OpenEye tool kits you are lucky I think!
Several bench mark is provided in the article and SMIRNOFF shows good performance.

New force field SMIRNOFF is simpler than other FF but powerful for describe feature of molecules.
I am looking forward to progress of the project and would like to think about the way deals with open source and industry.

If reader has interest in this FF, you can get it from the URL below.
https://github.com/openforcefield

Calculate HOMO and LUMO with Psi4 reviced #RDKit #Psi4

Yesterday, I got comments from reader.
Regarding the comment, to calculate HOMO LUMO with psi4 correct way is below.

import psi4
import numpy as np
from rdkit import Chem
from rdkit.Chem import AllChem
from rdkit.Chem.Draw import IPythonConsole
psi4.core.set_output_file("output1.dat", True)
def mol2xyz(mol):
    mol = Chem.AddHs(mol)
    AllChem.EmbedMolecule(mol, useExpTorsionAnglePrefs=True,useBasicKnowledge=True)
    AllChem.UFFOptimizeMolecule(mol)
    atoms = mol.GetAtoms()
    string = string = "\n"
    for i, atom in enumerate(atoms):
        pos = mol.GetConformer().GetAtomPosition(atom.GetIdx())
        string += "{} {} {} {}\n".format(atom.GetSymbol(), pos.x, pos.y, pos.z)
    string += "units angstrom\n"
    return string, mol

Next, calculate HOMO-LUMO of benzene with the function and psi4.

mol = Chem.MolFromSmiles("c1ccccc1")
xyz, mol=mol2xyz(mol)
psi4.set_memory('4 GB')
psi4.set_num_threads(4)
benz = psi4.geometry(xyz)
%time scf_e, scf_wfn = psi4.energy("B3LYP/cc-pVDZ", return_wfn=True)
> CPU times: user 13.8 s, sys: 226 ms, total: 14 s
> Wall time: 4.51 s

After the calculation, I could access HOMO-LUMO, the code is below.

# HOMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha()]
# LUMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha() + 1]
HOMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha()-1]
LUMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha()]
print(HOMO, LUMO, scf_e)
> -0.2529021800443842 -0.006506519238935586 -232.26252757817264

Check log file

!cat out2.dat

  Memory set to   3.725 GiB by Python driver.
  Threads set to 4 by Python driver.

*** tstart() called on takayukis-MacBook-Pro.local
*** at Mon Aug 27 22:26:56 2018

   => Loading Basis Set <=

    Name: CC-PVDZ
    Role: ORBITAL
    Keyword: BASIS
    atoms 1-6  entry C          line   138 file /Users/iwatobipen/.pyenv/versions/anaconda3-4.2.0/share/psi4/basis/cc-pvdz.gbs 
    atoms 7-12 entry H          line    22 file /Users/iwatobipen/.pyenv/versions/anaconda3-4.2.0/share/psi4/basis/cc-pvdz.gbs 

    There are an even number of electrons - assuming singlet.
    Specify the multiplicity in the molecule input block.


         ---------------------------------------------------------
                                   SCF
            by Justin Turney, Rob Parrish, Andy Simmonett
                             and Daniel Smith
                              RKS Reference
                        4 Threads,   3814 MiB Core
         ---------------------------------------------------------

  ==> Geometry <==

    Molecular point group: c1
    Full point group: C1

    Geometry (in Angstrom), charge = 0, multiplicity = 1:

       Center              X                  Y                   Z               Mass       
    ------------   -----------------  -----------------  -----------------  -----------------
         C            1.160791903590    -0.776928934439    -0.079150803890    12.000000000000
         C            1.255739388827     0.616792238521    -0.002681541758    12.000000000000
         C            0.094947479782     1.393721178119     0.076469246393    12.000000000000
         C           -1.160791914824     0.776928940041     0.079150771790    12.000000000000
         C           -1.255739387065    -0.616792248432     0.002681608472    12.000000000000
         C           -0.094947472815    -1.393721173263    -0.076469222838    12.000000000000
         H            2.058813166717    -1.377983059255    -0.140384154914     1.007825032070
         H            2.227214722117     1.093960079368    -0.004756245235     1.007825032070
         H            0.168401517636     2.471943131887     0.135627614553     1.007825032070
         H           -2.058813208566     1.377983069413     0.140383740077     1.007825032070
         H           -2.227214704360    -1.093960120700     0.004756292428     1.007825032070
         H           -0.168401463717    -2.471943107238    -0.135627939511     1.007825032070

  Running in c1 symmetry.

  Rotational constants: A =      0.18924  B =      0.18924  C =      0.09462 [cm^-1]
  Rotational constants: A =   5673.32397  B =   5673.32388  C =   2836.66196 [MHz]
  Nuclear repulsion =  203.019334728971273

  Charge       = 0
  Multiplicity = 1
  Electrons    = 42
  Nalpha       = 21
  Nbeta        = 21

  ==> Algorithm <==

  SCF Algorithm Type is DF.
  DIIS enabled.
  MOM disabled.
  Fractional occupation disabled.
  Guess Type is SAD.
  Energy threshold   = 1.00e-06
  Density threshold  = 1.00e-06
  Integral threshold = 0.00e+00

  ==> Primary Basis <==

  Basis Set: CC-PVDZ
    Blend: CC-PVDZ
    Number of shells: 54
    Number of basis function: 114
    Number of Cartesian functions: 120
    Spherical Harmonics?: true
    Max angular momentum: 2

  ==> DFT Potential <==

   => Composite Functional: B3LYP <= 

    B3LYP Hyb-GGA Exchange-Correlation Functional

    P. J. Stephens, F. J. Devlin, C. F. Chabalowski, and M. J. Frisch, J. Phys. Chem. 98, 11623 (1994)

    Deriv               =              1
    GGA                 =           TRUE
    Meta                =          FALSE

    Exchange Hybrid     =           TRUE
    MP2 Hybrid          =          FALSE

   => Exchange Functionals <=

    0.0800   Slater exchange
    0.7200         Becke 88

   => Exact (HF) Exchange <=

    0.2000               HF 

   => Correlation Functionals <=

    0.1900   Vosko, Wilk & Nusair (VWN5_RPA)
    0.8100   Lee, Yang & Parr

   => Molecular Quadrature <=

    Radial Scheme       =       TREUTLER
    Pruning Scheme      =           FLAT
    Nuclear Scheme      =       TREUTLER

    BS radius alpha     =              1
    Pruning alpha       =              1
    Radial Points       =             75
    Spherical Points    =            302
    Total Points        =         266172
    Total Blocks        =           2084
    Max Points          =            255
    Max Functions       =            114

   => Loading Basis Set <=

    Name: (CC-PVDZ AUX)
    Role: JKFIT
    Keyword: DF_BASIS_SCF
    atoms 1-6  entry C          line   121 file /Users/iwatobipen/.pyenv/versions/anaconda3-4.2.0/share/psi4/basis/cc-pvdz-jkfit.gbs 
    atoms 7-12 entry H          line    51 file /Users/iwatobipen/.pyenv/versions/anaconda3-4.2.0/share/psi4/basis/cc-pvdz-jkfit.gbs 

  ==> Pre-Iterations <==

   -------------------------------------------------------
    Irrep   Nso     Nmo     Nalpha   Nbeta   Ndocc  Nsocc
   -------------------------------------------------------
     A        114     114       0       0       0       0
   -------------------------------------------------------
    Total     114     114      21      21      21       0
   -------------------------------------------------------

  ==> Integral Setup <==

  DFHelper Memory: AOs need 0.070 [GiB]; user supplied 2.794 [GiB]. Using in-core AOs.

  ==> MemDFJK: Density-Fitted J/K Matrices <==

    J tasked:                   Yes
    K tasked:                   Yes
    wK tasked:                   No
    OpenMP threads:               4
    Memory (MB):               2861
    Algorithm:                 Core
    Schwarz Cutoff:           1E-12
    Mask sparsity (%):       0.3693
    Fitting Condition:        1E-12

   => Auxiliary Basis Set <=

  Basis Set: (CC-PVDZ AUX)
    Blend: CC-PVDZ-JKFIT
    Number of shells: 198
    Number of basis function: 558
    Number of Cartesian functions: 636
    Spherical Harmonics?: true
    Max angular momentum: 3

  Minimum eigenvalue in the overlap matrix is 3.7184237071E-04.
  Using Symmetric Orthogonalization.

  SCF Guess: Superposition of Atomic Densities via on-the-fly atomic UHF.

  ==> Iterations <==

                           Total Energy        Delta E     RMS |[F,P]|

   @DF-RKS iter   0:  -232.99504225236745   -2.32995e+02   7.10044e-02 
   @DF-RKS iter   1:  -232.10322360969730    8.91819e-01   8.92096e-03 
   @DF-RKS iter   2:  -232.08890690303650    1.43167e-02   9.91157e-03 DIIS
   @DF-RKS iter   3:  -232.26148696855563   -1.72580e-01   7.72966e-04 DIIS
   @DF-RKS iter   4:  -232.26244386501853   -9.56896e-04   1.55832e-04 DIIS
   @DF-RKS iter   5:  -232.26249567324737   -5.18082e-05   1.40053e-04 DIIS
   @DF-RKS iter   6:  -232.26252736183829   -3.16886e-05   1.12370e-05 DIIS
   @DF-RKS iter   7:  -232.26252757817264   -2.16334e-07   5.75991e-07 DIIS

  ==> Post-Iterations <==

    Orbital Energies [Eh]
    ---------------------

    Doubly Occupied:                                                      

       1A    -10.190567     2A    -10.190357     3A    -10.190356  
       4A    -10.189878     5A    -10.189877     6A    -10.189659  
       7A     -0.851906     8A     -0.745429     9A     -0.745428  
      10A     -0.602584    11A     -0.602584    12A     -0.521871  
      13A     -0.463024    14A     -0.444273    15A     -0.421160  
      16A     -0.421159    17A     -0.365359    18A     -0.344262  
      19A     -0.344262    20A     -0.252905    21A     -0.252902  

    Virtual:                                                              

      22A     -0.006507    23A     -0.006506    24A      0.059666  
      25A      0.099451    26A      0.099452    27A      0.133761  
      28A      0.133764    29A      0.150228    30A      0.153828  
      31A      0.277077    32A      0.277080    33A      0.295653  
      34A      0.295656    35A      0.405118    36A      0.408148  
      37A      0.464413    38A      0.465367    39A      0.512461  
      40A      0.512464    41A      0.517424    42A      0.517430  
      43A      0.519856    44A      0.519868    45A      0.526820  
      46A      0.540745    47A      0.592924    48A      0.592924  
      49A      0.647786    50A      0.647787    51A      0.650076  
      52A      0.650083    53A      0.667968    54A      0.720592  
      55A      0.788201    56A      0.828354    57A      0.857690  
      58A      0.883159    59A      0.883161    60A      0.924558  
      61A      0.992120    62A      0.992122    63A      1.005964  
      64A      1.005973    65A      1.011555    66A      1.011587  
      67A      1.059132    68A      1.071624    69A      1.071625  
      70A      1.216812    71A      1.280232    72A      1.280245  
      73A      1.456675    74A      1.476446    75A      1.476447  
      76A      1.510782    77A      1.538630    78A      1.598096  
      79A      1.598099    80A      1.606414    81A      1.606425  
      82A      1.633651    83A      1.682795    84A      1.682801  
      85A      1.692381    86A      1.692388    87A      1.725702  
      88A      1.795113    89A      1.795115    90A      1.839139  
      91A      1.839159    92A      1.844378    93A      1.848385  
      94A      1.848386    95A      1.883194    96A      1.981556  
      97A      1.981559    98A      1.989993    99A      1.990001  
     100A      2.021139   101A      2.191006   102A      2.261460  
     103A      2.371980   104A      2.426824   105A      2.426829  
     106A      2.435274   107A      2.435279   108A      2.641049  
     109A      2.641053   110A      2.695891   111A      2.795913  
     112A      2.914328   113A      2.914351   114A      3.646462  

    Final Occupation by Irrep:
              A 
    DOCC [    21 ]

  Energy converged.

  @DF-RKS Final Energy:  -232.26252757817264

   => Energetics <=

    Nuclear Repulsion Energy =            203.0193347289712733
    One-Electron Energy =                -713.2777384427657807
    Two-Electron Energy =                 306.1488686089047064
    DFT Exchange-Correlation Energy =     -28.1529924732828292
    Empirical Dispersion Energy =           0.0000000000000000
    VV10 Nonlocal Energy =                  0.0000000000000000
    Total Energy =                       -232.2625275781726373



Properties will be evaluated at   0.000000,   0.000000,   0.000000 [a0]

Properties computed using the SCF density matrix

  Nuclear Dipole Moment: [e a0]
     X:     0.0000      Y:    -0.0000      Z:    -0.0000

  Electronic Dipole Moment: [e a0]
     X:     0.0000      Y:    -0.0000      Z:     0.0000

  Dipole Moment: [e a0]
     X:     0.0000      Y:    -0.0000      Z:    -0.0000     Total:     0.0000

  Dipole Moment: [D]
     X:     0.0000      Y:    -0.0000      Z:    -0.0000     Total:     0.0000


*** tstop() called on takayukis-MacBook-Pro.local at Mon Aug 27 22:27:00 2018
Module time:
	user time   =      13.71 seconds =       0.23 minutes
	system time =       0.22 seconds =       0.00 minutes
	total time  =          4 seconds =       0.07 minutes
Total time:
	user time   =      27.58 seconds =       0.46 minutes
	system time =       0.47 seconds =       0.01 minutes
	total time  =         32 seconds =       0.53 minutes

That’s all. I am happy because I can get many response through the my blog post and I can have many opportunity to learn many things.

Enjoy summer vacation

I and my family enjoyed camp in this weekend. This is third time for us.
The campsite is located near the river. Kids enjoyed playing in the water and caught crabs.

This tent site was very humid because after a typhoon has passed. It was
terrible dew condenses on the tent….

In this morning, I enjoyed coffee and hot sand. My new partner, coleman 413H 2 burner worked very well. It made us delicious breakfast. ;-)

I would like to go camp again near the feature!

Calculate HOMO and LUMO with Psi4 #RDKit #Psi4

You know Psi4 is an open-source suite of ab initio quantum chemistry programs designed for efficient, high-accuracy simulations of a variety of molecular properties. It is very easy to use and has an optional Python interface.
It is useful for us I think. Because Psi4 can use in python, it means we can integrate many libraries in python!  And it is worth to know that, to communicate numpy and psi4 is very easy.

Today, I conducted HOMO LUMO calculation with Psi4 and RDKit.

HOMO-LUMO gap is often used to estimate risk of drug-induced phototoxicity.

Let's start! ;-)

At first, import libraries and define the mol2xyz function. The function generates a conformation and converts RDKit mol object to xyz format.

psi4.core.set_output_file(“output1.dat”, True) is used to logging.

import psi4
import numpy as np
from rdkit import Chem
from rdkit.Chem import AllChem
from rdkit.Chem.Draw import IPythonConsole
psi4.core.set_output_file("output1.dat", True)
def mol2xyz(mol):
    mol = Chem.AddHs(mol)
    AllChem.EmbedMolecule(mol, useExpTorsionAnglePrefs=True,useBasicKnowledge=True)
    AllChem.UFFOptimizeMolecule(mol)
    atoms = mol.GetAtoms()
    string = "\n"
    for i, atom in enumerate(atoms):
        pos = mol.GetConformer().GetAtomPosition(atom.GetIdx())
        string += "{} {} {} {}\n".format(atom.GetSymbol(), pos.x, pos.y, pos.z)
    string += "units angstrom\n"
    return string, mol

Next, calculate HOMO-LUMO of benzene with the function and psi4.

mol = Chem.MolFromSmiles("c1ccccc1")
xyz, mol=mol2xyz(mol)
psi4.set_memory('4 GB')
psi4.set_num_threads(4)
benz = psi4.geometry(xyz)
%time scf_e, scf_wfn = psi4.energy("B3LYP/cc-pVDZ", return_wfn=True)
>CPU times: user 13.5 s, sys: 207 ms, total: 13.7 s
>Wall time: 4.46 s

I set return_wfn argument is True because I want to get wave function information.
Energy calculation need many CPU time. To perform many compound calculation, I need more machine power!

After the calculation, I could access HOMO-LUMO, the code is below.

HOMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha()]
LUMO = scf_wfn.epsilon_a_subset('AO', 'ALL').np[scf_wfn.nalpha() + 1]
print(HOMO, LUMO, scf_e)
>-0.006507529999155065 -0.006506586740442874 -232.26253075556204

Yah, easy… But the value is quite different from some literatures. Hmm Am I wrong ? Maybe yes…
Any advice and suggestions will be greatly appreciated.

It is very easy to check log.
I am reading API and reference of Psi4 now!

!cat out.dat

 Memory set to   3.725 GiB by Python driver.
  Threads set to 4 by Python driver.

  Memory set to   3.725 GiB by Python driver.
  Threads set to 4 by Python driver.

*** tstart() called on ********
*** at Fri Aug 24 22:21:33 2018

   => Loading Basis Set <=

    Name: CC-PVDZ
    Role: ORBITAL
    Keyword: BASIS
---------snip------------

    There are an even number of electrons - assuming singlet.
    Specify the multiplicity in the molecule input block.


         ---------------------------------------------------------
                                   SCF
            by Justin Turney, Rob Parrish, Andy Simmonett
                             and Daniel Smith
                              RKS Reference
                        4 Threads,   3814 MiB Core
         ---------------------------------------------------------

  ==> Geometry <==

    Molecular point group: c1
    Full point group: C1

    Geometry (in Angstrom), charge = 0, multiplicity = 1:

       Center              X                  Y                   Z               Mass       
    ------------   -----------------  -----------------  -----------------  -----------------
         C            0.806497703012    -1.143092245995     0.014915282772    12.000000000000
         C            1.393280339340     0.126835003153    -0.002136692164    12.000000000000
         C            0.586782120312     1.269928194219    -0.017051393298    12.000000000000
         C           -0.806497629817     1.143092609376    -0.014913861108    12.000000000000
         C           -1.393280087652    -0.126835526704     0.002137132311    12.000000000000
         C           -0.586782336814    -1.269927969465     0.017053614836    12.000000000000
         H            1.430428517155    -2.027419681898     0.026439293008     1.007825032070
         H            2.471161063731     0.224955697903    -0.003795091078     1.007825032070
         H            1.040731718362     2.252381167101    -0.030251698606     1.007825032070
         H           -1.430425978428     2.027420563468    -0.026458153907     1.007825032070
         H           -2.471160894666    -0.224959372018     0.003781521713     1.007825032070
         H           -1.040735716617    -2.252379143548     0.030235509138     1.007825032070

  Running in c1 symmetry.

  Rotational constants: A =      0.18924  B =      0.18924  C =      0.09462 [cm^-1]
  Rotational constants: A =   5673.32470  B =   5673.32274  C =   2836.66186 [MHz]
  Nuclear repulsion =  203.019333245138824

  Charge       = 0
  Multiplicity = 1
  Electrons    = 42
  Nalpha       = 21
  Nbeta        = 21

  ==> Algorithm <==

  SCF Algorithm Type is DF.
  DIIS enabled.
  MOM disabled.
  Fractional occupation disabled.
  Guess Type is SAD.
  Energy threshold   = 1.00e-06
  Density threshold  = 1.00e-06
  Integral threshold = 0.00e+00

  ==> Primary Basis <==

  Basis Set: CC-PVDZ
    Blend: CC-PVDZ
    Number of shells: 54
    Number of basis function: 114
    Number of Cartesian functions: 120
    Spherical Harmonics?: true
    Max angular momentum: 2

  ==> DFT Potential <==

   => Composite Functional: B3LYP <= 

    B3LYP Hyb-GGA Exchange-Correlation Functional

    P. J. Stephens, F. J. Devlin, C. F. Chabalowski, and M. J. Frisch, J. Phys. Chem. 98, 11623 (1994)

    Deriv               =              1
    GGA                 =           TRUE
    Meta                =          FALSE

    Exchange Hybrid     =           TRUE
    MP2 Hybrid          =          FALSE

   => Exchange Functionals <=

    0.0800   Slater exchange
    0.7200         Becke 88

   => Exact (HF) Exchange <=

    0.2000               HF 

   => Correlation Functionals <=

    0.1900   Vosko, Wilk & Nusair (VWN5_RPA)
    0.8100   Lee, Yang & Parr

   => Molecular Quadrature <=

    Radial Scheme       =       TREUTLER
    Pruning Scheme      =           FLAT
    Nuclear Scheme      =       TREUTLER

    BS radius alpha     =              1
    Pruning alpha       =              1
    Radial Points       =             75
    Spherical Points    =            302
    Total Points        =         266204
    Total Blocks        =           2062
    Max Points          =            256
    Max Functions       =            114

   => Loading Basis Set <=

    Name: (CC-PVDZ AUX)
    Role: JKFIT
    Keyword: DF_BASIS_SCF
-----snip--------
  ==> Pre-Iterations <==

   -------------------------------------------------------
    Irrep   Nso     Nmo     Nalpha   Nbeta   Ndocc  Nsocc
   -------------------------------------------------------
     A        114     114       0       0       0       0
   -------------------------------------------------------
    Total     114     114      21      21      21       0
   -------------------------------------------------------

  ==> Integral Setup <==

  DFHelper Memory: AOs need 0.070 [GiB]; user supplied 2.794 [GiB]. Using in-core AOs.

  ==> MemDFJK: Density-Fitted J/K Matrices <==

    J tasked:                   Yes
    K tasked:                   Yes
    wK tasked:                   No
    OpenMP threads:               4
    Memory (MB):               2861
    Algorithm:                 Core
    Schwarz Cutoff:           1E-12
    Mask sparsity (%):       0.3693
    Fitting Condition:        1E-12

   => Auxiliary Basis Set <=

  Basis Set: (CC-PVDZ AUX)
    Blend: CC-PVDZ-JKFIT
    Number of shells: 198
    Number of basis function: 558
    Number of Cartesian functions: 636
    Spherical Harmonics?: true
    Max angular momentum: 3

  Minimum eigenvalue in the overlap matrix is 3.7184246400E-04.
  Using Symmetric Orthogonalization.

  SCF Guess: Superposition of Atomic Densities via on-the-fly atomic UHF.

  ==> Iterations <==

                           Total Energy        Delta E     RMS |[F,P]|

   @DF-RKS iter   0:  -232.98648910745848   -2.32986e+02   7.09616e-02 
   @DF-RKS iter   1:  -232.10265029904261    8.83839e-01   8.93885e-03 
   @DF-RKS iter   2:  -232.08812748497797    1.45228e-02   9.76151e-03 DIIS
   @DF-RKS iter   3:  -232.26148987002321   -1.73362e-01   7.73194e-04 DIIS
   @DF-RKS iter   4:  -232.26244676165251   -9.56892e-04   2.20816e-04 DIIS
   @DF-RKS iter   5:  -232.26249884952190   -5.20879e-05   1.40071e-04 DIIS
   @DF-RKS iter   6:  -232.26253054068945   -3.16912e-05   1.12245e-05 DIIS
   @DF-RKS iter   7:  -232.26253075556204   -2.14873e-07   5.66817e-07 DIIS

  ==> Post-Iterations <==

    Orbital Energies [Eh]
    ---------------------

    Doubly Occupied:                                                      

       1A    -10.190570     2A    -10.190360     3A    -10.190358  
       4A    -10.189881     5A    -10.189879     6A    -10.189662  
       7A     -0.851912     8A     -0.745431     9A     -0.745426  
      10A     -0.602585    11A     -0.602585    12A     -0.521876  
      13A     -0.463024    14A     -0.444275    15A     -0.421161  
      16A     -0.421155    17A     -0.365362    18A     -0.344264  
      19A     -0.344262    20A     -0.252907    21A     -0.252901  

    Virtual:                                                              

      22A     -0.006508    23A     -0.006507    24A      0.059658  
      25A      0.099450    26A      0.099455    27A      0.133761  
      28A      0.133763    29A      0.150228    30A      0.153828  
      31A      0.277076    32A      0.277078    33A      0.295654  
      34A      0.295658    35A      0.405112    36A      0.408146  
      37A      0.464412    38A      0.465356    39A      0.512461  
      40A      0.512461    41A      0.517423    42A      0.517433  
      43A      0.519852    44A      0.519872    45A      0.526750  
      46A      0.540745    47A      0.592922    48A      0.592924  
      49A      0.647783    50A      0.647787    51A      0.650079  
      52A      0.650080    53A      0.667968    54A      0.720591  
      55A      0.788173    56A      0.828353    57A      0.857688  
      58A      0.883160    59A      0.883161    60A      0.924558  
      61A      0.992121    62A      0.992123    63A      1.005962  
      64A      1.005979    65A      1.011551    66A      1.011617  
      67A      1.059133    68A      1.071623    69A      1.071625  
      70A      1.216802    71A      1.280227    72A      1.280249  
      73A      1.456674    74A      1.476443    75A      1.476447  
      76A      1.510781    77A      1.538598    78A      1.598094  
      79A      1.598098    80A      1.606419    81A      1.606454  
      82A      1.633651    83A      1.682793    84A      1.682805  
      85A      1.692380    86A      1.692389    87A      1.725701  
      88A      1.795112    89A      1.795115    90A      1.839139  
      91A      1.839180    92A      1.844376    93A      1.848382  
      94A      1.848384    95A      1.883194    96A      1.981552  
      97A      1.981560    98A      1.989989    99A      1.990002  
     100A      2.021138   101A      2.191006   102A      2.261459  
     103A      2.371976   104A      2.426825   105A      2.426828  
     106A      2.435277   107A      2.435291   108A      2.641052  
     109A      2.641053   110A      2.695891   111A      2.795915  
     112A      2.914318   113A      2.914347   114A      3.646453  

    Final Occupation by Irrep:
              A 
    DOCC [    21 ]

  Energy converged.

  @DF-RKS Final Energy:  -232.26253075556204

   => Energetics <=

    Nuclear Repulsion Energy =            203.0193332451388244
    One-Electron Energy =                -713.2776809379226961
    Two-Electron Energy =                 306.1488028199291875
    DFT Exchange-Correlation Energy =     -28.1529858827073518
    Empirical Dispersion Energy =           0.0000000000000000
    VV10 Nonlocal Energy =                  0.0000000000000000
    Total Energy =                       -232.2625307555620680



Properties will be evaluated at   0.000000,   0.000000,   0.000000 [a0]

Properties computed using the SCF density matrix

  Nuclear Dipole Moment: [e a0]
     X:    -0.0000      Y:    -0.0000      Z:    -0.0000

  Electronic Dipole Moment: [e a0]
     X:     0.0000      Y:    -0.0000      Z:     0.0000

  Dipole Moment: [e a0]
     X:    -0.0000      Y:    -0.0000      Z:    -0.0000     Total:     0.0000

  Dipole Moment: [D]
     X:    -0.0000      Y:    -0.0000      Z:    -0.0000     Total:     0.0000


*** tstop() ********l at Fri Aug 24 22:21:37 2018
Module time:
	user time   =      13.48 seconds =       0.22 minutes
	system time =       0.21 seconds =       0.00 minutes
	total time  =          4 seconds =       0.07 minutes
Total time:
	user time   =      13.48 seconds =       0.22 minutes
	system time =       0.21 seconds =       0.00 minutes
	total time  =          4 seconds =       0.07 minutes

​

Dual Kinase inhibitor for Autoimmune disease

There are lots of JAK/TYK inhibitor project in drug discovery area.
https://www.ncbi.nlm.nih.gov/pubmed/30113844
Here is an article from pfizer. Pfizer discovered and launched JAK inhibitor ‘tofacitinib’.
Tofacitinib inhibits JAK3, JAK1 and JAK3.

It is well known that JAK2 uniquely forms a homodimer, which is important in hematopoiesis via signal transduction associated with erythropoietin (EPO), thrombopoietin (TPO), and IL-3. Inhibition of JAK2 is concerned about reduction in hemoglobin/Amemia.

They focused to obtain JAK1/TYK2 dual inhibitor to block INF alpha. I think the strongest point is that they can use PK/PD relationship of tofacinib’s JAK2 inhibition.
By using their clinical knowledge, they could define the clear criteria of the project.

Their lead compound is pyrimidine derivative with 4 diversity points. They changed R4 group from cyanoacetyl group to cyclopropyamidel group to improve hydrohobic interactions. And finally they found difluoro cyclopropyl amide moiety. Genentec published Tyk2 inhibitor and the compound has cyclopropyl moiety too but different binding mode. Hmm, cyclopropyl group is interesting parts for medicinal chemist.

Finally they found compound 23 and the compound showed good efficacy in vivo AIA model (PF-06700841). And this compound studies in Ph II trials now.

BTW, In fig1 shows Jak inhibitors on the market and in late stage clinical development.

“””
It is very interesting for me baricitinib and ruxolitinib is quite similar structure. It is because that both compounds are developed by same company Incyte Biopharmaceutical Company. I did not check patents of both compounds. I would like to know claim strategy of them.
https://pdfs.semanticscholar.org/8184/fef3e8864e14aa652f01f237e6b4df9ec86a.pdf?_ga=2.218333145.1597951041.1535025783-1067331720.1532781359
“””

第17回 サマーカップinエコパの応援行った #ドッジボール

 長男が所属しているドッチボールチームの参加する大会、第17回 サマーカップinエコパ ということで、掛川のエコパアリーナまで応援に行ってきました。
http://www.shizuoka-dba.com/keikaku.html
 今年は低学年の入団者が多く、オフィシャル1チーム、ジュニア2チーム、計3チームでの参戦でした。長男はチームに所属してちょうど一年くらい。今回はジュニア、1,2年生メインのチームでアタッカーとして頑張っていました。
ドッジボールのジュニアは4年生以下の小学生で構成されます。4年生がいるチームと比べると今回のチームはまだまだ小柄な子が多く、予選リーグを突破することはかないませんでしたが、高学年相手に果敢にボールを投げアウトを取ったり、相手のボールをキャッチしている姿を見ると、家でがグズグズしてるが成長してきたなって思いました。
他の子も、みんな元気に頑張ってました。頼もしい!

 オフィシャルともう一つのジュニアはいずれも決勝リーグに勝ち残りましたが、残念ながら優勝には届かず。チームの仲間と力を合わせて勝利を目指す姿を見るのはこっちも元気をもらって、とても楽しいものです。

 豪速球を投げるエースがいるチームは迫力がありますし強いですがそれだけでは勝ち残れないのがまた面白いところ。5分という短い時間での逆転劇などスリルもあるし面白い。

まだまだ暑い夏が続きますが、体調を崩さず元気に楽しく頑張ってほしいものです。
私も負けないように走りこんで体力つけないと!

Expand opportunity to accessing new building blocks

Building Block(BB) is key part of medicinal chemistry. Advances in science medicinal chemists can have opportunity to access novel BBs and they do not consider how to make BBs these days.
In my personal opinion, unique BB will be the strong point of the their company. So medchem need to pay a lot of effort to designing and synthesis of new BB. In particular we often introduce fluorine atom to improve target potency, ADMET and physchem properties of molecule however introduction of fluorine atom in the desired position of the molecule is difficult. It is worth if there are lots of commercial available fluorinated BBs.

By the way, recently risk sharing model such as HTS library sharing, collaborative research model is spreading idea among pharmaceutical companies.
I found new approach reported from pfizer.
Here is an effort of pfizer.
https://www.ncbi.nlm.nih.gov/pubmed/29571837
The article is focused on fluorinated BB. The authors developed cross-pharma vendor buying group. The Buying group seek a single vendor, purchase BB from the vendor.

The pros of the model is that the group company can access novel, unpublished 1g of BBs with effective cost and have opportunity to discuss nature, concept of new BBs. This system is not fully exclusive but has 6 months advantage before publication.

It can not only reduce the cost of accessing BB but also can reduce the accessibility of complex fluorinated BBs.

Joint purchase model seems work well for same scale size of big pharma I think. I would like to know that whether dose the system work well for mid- small- size of pharma.