 |
PDBsum entry 2v3h
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
2v3h
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Fluorine in pharmaceuticals: looking beyond intuition.
|
|
|
Authors
|
|
K.Müller,
C.Faeh,
F.Diederich.
|
|
|
Ref.
|
|
Science, 2007,
317,
1881-1886.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Fluorine substituents have become a widespread and important drug component,
their introduction facilitated by the development of safe and selective
fluorinating agents. Organofluorine affects nearly all physical and adsorption,
distribution, metabolism, and excretion properties of a lead compound. Its
inductive effects are relatively well understood, enhancing bioavailability, for
example, by reducing the basicity of neighboring amines. In contrast,
exploration of the specific influence of carbon-fluorine single bonds on docking
interactions, whether through direct contact with the protein or through
stereoelectronic effects on molecular conformation of the drug, has only
recently begun. Here, we review experimental progress in this vein and add
complementary analysis based on comprehensive searches in the Cambridge
Structural Database and the Protein Data Bank.
|
|
|
|
|
|
|
|
Figure 3.
Fig. 3. (A) Aryl–OCHF[2] fragment (  = 19°) of
roflumilast bound to phosphordiesterase 4 (table S1, entry 7)
shows a multipolar C–F···C=O contact with
the backbone amide of Trp332. (B) Aryl–OCF[3] fragment ( =
81°) of an inhibitor bound to the Ser protease trypsin
(table S1, entry 13). Protein Cs are shown in gray (also applies
to Fig. 5 and the SOM).
|
|
Figure 5.
Fig. 5. (A) Fluorine interacts favorably with peptidic N–H
(ligand Cs in green) and C=O (ligand Cs in purple) moieties. (B)
Fluorine undergoes dipolar interactions with side-chain amides
of Gln and Asp (ligand Cs in yellow). (C) The C–F residue of a
tricyclic inhibitor undergoes a multipolar interaction with the
backbone C=O of Asn98 in the D pocket of thrombin (table S1,
entry 23). (D) A dipolar N–H···F–C
interaction induces the shown conformation of a thrombin
inhibitor within the enzyme (fig. S3 and table S1, entry 22).
|
|
|
|
|
|
The above figures are
reprinted
by permission from the AAAs:
Science
(2007,
317,
1881-1886)
copyright 2007.
|
|
|
|
|
|
|
