When we calculate HSP of molecules, we use SMILES molecular structure.
If we want calculate COVID-19 medicine with separated 3 parts, we need 3 SMILES structures.
JSME molecular drawing tool is included in HSPiP software.
Once you draw molecule, then you will obtain SMILES structure and with it, you will get HSP of that molecule.
For Pfizer’s PF-07321332 PAXLOVID, we easily obtain SMILES: CC(C)(C)C(NC(=O)C(F)(F)F)C(=O)N1CC3C(C1C(=O)NC(C#N)CC2CCNC2=O)C3(C)C
Then break molecule into 3 parts. Break the bonds, and add methyl group.
You will get 3 molecules.
In SMILES notation, each molecule’s SMILES are separated by period like,
CC1C2C(CN1C(=O)C(NC(=O)C(F)(F)F)C(C)(C)C)C2(C)C.CNC(C)=O.CC(C#N)CC1CCNC1=O
Then you get 3 SMILES and 3 HSPs after you calculate with YMB.
left:CC1C2C(CN1C(=O)C(NC(=O)C(F)(F)F)C(C)(C)C)C2(C)C
center:CNC(C)=O
right:CC(C#N)CC1CCNC1=O
OK, then let’s think of Bioisostere.
The center molecule is Amide.
From the point of Bioisostere, Amide can be substitute by these Functional Groups.
So, break bond and set X or D(deuterium) something we can easily find out.
Left: CC(C)(C)C(NC(=O)C(F)(F)F)C(=O)N1CC2C(C2(C)C)C1[X]
Center:
[X]C(O)C[X]
[X]C(=O)C(F)(F)[X]
[X]C(F)=C[X]
[X]C1(CC1)N[X]
[X]C(C(F)(F)F)N[X]
[X]S(=O)(=O)N[X]
[X]c1oc(nn1)[X]
[X]n1nnc(c1)[X]
[X]c1noc(n1)[X]
Right: [X]C(C#N)CC1C(NCC1)=O
Then build molecule.
CC(C)(C)C(NC(=O)C(F)(F)F)C(=O)N1CC2C(C2(C)C)C1[X] [X]C(O)C[X] [X]C(C#N)CC1C(NCC1)=O
If you delete 2 pair of [X][X] then you will obtain new molecule.
It is the just String operation. You can do it even with Excel.
There are 4 amides in this molecule.
And Amide and Ester + 9 Functional groups are exist.
So, 11*11*11*11 molecules can be build.
If you have CLI(Command Line Interface) license of HSPiP, you can run the all calculation with batch. Maybe it take 30 min. for all calculation.
And not only HSPs, (Donor Number, Acceptor Number, in 2021 version) logKow, logS(solubility to water) or other Descriptors are also calculated.
Yet, some of the utility to put X left (right) side or put 2 X both end is needed.
Some of the CLI users start to use this utility and preview of YMB-2021 version.
Please looking forward to releasing new version of HSPiP.