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The Sigma-Aldrich screening collection has been parsed into amines that are either primary, secondary or tertiary. These have been further parsed based on formal charge on the molecule. Finally, 3D structures have been calculated with Gaussian (AM1), and structures were docked into CYP2D6 using Autodock and the binding score was recomputed using X-SCORE Properties (esp. pKa) and druglike scores were calculated with Pipeline PilotTM (SciTegic, Inc.). Since CYP2D6 is the major Cytochrome P450 that metabolizes drugs with positively charged amines, the docking energies provide Medicinal Chemists with data to help them bias their choice of drug building blocks against molecules likely to be metabolized by or to inhibit this CYP. Structures of AM1 minimized compounds are visible from the website by clicking on the 2D image of the molecule. The lowest energy (of 10) docked structures is also visible by clicking on the Autodock energy values and also all ten structures are visible by clicking on the index number (last column). To simplify viewing, only docked ligand and heme are shown - to view the full protein, you merely need to load also the coordinates for the homology modeled CYP2D6. Warning:
to see 3D structures, you need the Chime plugin from MDL
!!
Note: Failed
structural calculations (just few of them) are indicated by the presence of either "buckyball",
or of just the CYP2D6 heme with no amine present and an X mark for Autodock and X-Score values.
Autodock values for docked energy are in Kcal/mol units. X-Score values are in pKd units.
For X-Score you have to multiply that value with -2.303RT (or -1.363666) to get the values in Kcal/mol units.
Primaryamines
ZippedSD File
Autodock
X-Score
Druglikeness
L:
FC = +2 Formal charge +2 for "L" library.
L:
FC = +3 Formal charge +3 for "L" library.
---------------------------------------------------------
R:
FC = -3 Formal charge -3 for "R" library.
R:
FC = -1 Formal charge -1 for "R" library.
R:
FC = 0 Formal charge 0 for "R" library.
R:
FC = +1 Formal charge +1 for "R" library.
R:
FC = +2 Formal charge +2 for "R" library.
R:
FC = +3 Formal charge +3 for "R" library.
R:
FC = +4 Formal charge +4 for "R" library.
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Secondary amines
ZippedSD File
Autodock
X-Score
Druglikeness
L:
FC = -1 Formal charge -1 for "L" library.
L:
FC = 0 Formal charge 0 for "L" library.
L:
FC = +1 Formal charge +1 for "L" library.
L:
FC = +2 Formal charge +2 for "L" library.
L:
FC = +3 Formal charge +3 for "L" library.
---------------------------------------------------------
R:
FC = -1 Formal charge -1 for "R" library.
R:
FC = 0 Formal charge 0 for "R" library.
R:
FC = +1 Formal charge +1 for "R" library.
R:
FC = +2 Formal charge +2 for "R" library.
R:
FC = +3 Formal charge +3 for "R" library.
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Tertiary amines
ZippedSD File
Autodock
X-Score
Druglikeness
L:
FC = -3 Formal charge -3 for "L" library.
L:
FC = 0 Formal charge 0 for "L" library.
L:
FC = +1 Formal charge +1 for "L" library.
L:
FC = +2 Formal charge +2 for "L" library.
L:
FC = +4 Formal charge +4 for "L" library.
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R:
FC = -6 Formal charge -6 for "R" library.
R:
FC = -4 Formal charge -4 for "R" library.
R:
FC = -3 Formal charge -3 for "R" library.
R:
FC = -2 Formal charge -2 for "R" library.
R:
FC = -1 Formal charge -1 for "R" library.
R:
FC = 0 Formal charge 0 for "R" library.
R:
FC = +1 Formal charge +1 for "R" library.
R:
FC = +2 Formal charge +2 for "R" library.
R:
FC = +4 Formal charge +4 for "R" library.
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Homology Modeled CYP2D6
Codeine Docked in CYP2D6
The CPFM has as part
of its mission, the goal of providing tools to help Medicinal Chemists
design protein inhibitors more effectively, either as drug leads or as
tools for studying protein function. To learn more about the CPFM, visit
our website at CPFM .
This work was sponsored in part by Sigma-Aldrich.
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