Foye's Principles of Medicinal Chemistry (Lemke, Foye's Principles of Medicinal Chemistry)

2293 Pages·2007·65.13 MB·English

by  Thomas L. Lemke, David A. Williams

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Color Section
Fig. 3.1. Visualization of a drug molecule N-(4-hydroxy-
phenyl)-acetamide (Tylenol or acetaminophen) computerized with
different levels of graphic representations. (A) Molecular structure of the
drug Tylenol. (B) Ball-stick model showing atomic positions and types.
(C) Ball-stick model with van der Waals dot surfaces. (D) Space-fil led
model showing van der Walls radii of the oxygen, nitrogen, and carbon
atoms. (E) Solvent accessible surface model (sol id) (solvent radius,
1.4Å). (See black and white image.)
Fig. 3.3. Graphic visualization of molecular orbital surface
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HOMO/LUMO calculation for the drug molecule acetaminophen. (See
black and white image.)
Fig. 3.7. Nuclear magnetic resonance NOE-constrained molecular
dynamics/molecular mechanics structure calculation of (A) the
polypeptides CB2I298-K319; (B) the amino acid backbone
superimposition of 10 low-energy conformers; (C) the cyl inder
representation with a turn at the fifth residue, arginine; (d) and the
ribbon display of the two helical segments, showing a curve side chain
of Arg302 forming a salt bridge (green l ine) with Glu305. (See black
and white image.)
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Fig. 3.8. A workflow of in sil ico virtual screening process: receptor-based
and l igand-based approaches. (See black and white image.)
Fig. 3.9. Three-dimensional G protein–coupled CB2 receptor structure
(right) constructed by homology and multiple sequence al ignment
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method (left), including the seven transmembrane helices (cyl inders,
I–VII) and loop regions (ribbons). (From Xie XQ, Chen JZ, Bil l ings EM.
3D structural model of the G protein–coupled cannabinoid CB2 receptor.
Proteins: Structure, Function, and Genetics 2003;53:307–319; with
permission.) (See black and white image.)
Fig. 3.10. MOLCAD-predicted CB2-binding pocket surrounded by active
amino acid residues, showing an amphipathic contour, hydrophil ic center
(blue), and hydrophobic cleft (brown). The site-directed mutagenesis–
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detected binding residues are color-coded in terms of their distance to
the pocket (magenta > yel low > green > blue) as the interaction weakens.
(See black and white image.)
Fig. 3.11. CoMFA contour maps for arylpyrazole antagonists of
cannabinoid receptor subtypes CB1 (A) and CB2 (B). Sterical ly favored
areas (contribution level, 80%) are shown in green. Sterical ly unfavored
areas (contribution level, 20%) are shown in yel low, and positive-
potential favored areas (contribution level, 80%) are shown in blue.
Positive-potential unfavored areas (contribution level, 20%) are shown in
red. Plots of the corresponding CoMFA-calculated and experimental
values of binding affinity (given as pKi) of arylpyrazole compounds at
CB1 (AA) and CB2 (BB) receptor, respectively are shown as well .
(Adapted with permission from Chen J, Han X, Lan R, et al. 3D-QSAR
studies of arylpyrazole antagonists of cannabinoid receptor subtypes
CB1 and CB2. A combined NMR and CoMFA approach. J Med Chem
2006;49:625–636; with permission.) (See black and white image.)
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Fig. 17.4. Ribbon diagram of monomeric PDE4D2 (PDB 1PTW).
5′-AMP is shown as balls-and-sticks, whereas two divalent metal icons
are shown as sol id spheres. (From Manallack DT, Hughes RA,
Thompson PE. The next generation of phosphodiesterase inhibitors:
structural clues to l igand and substrate selectivity of
phosphodiesterases. J Med Chem 2005;48:3449–6342; with
permission.) (See black and white image.)
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Fig. 17.5. Surface representation showing 5′-AMP in the nucleotide
binding pocket of PDE4D2 (PDB 1PTW). 5′-AMP is shown as balls-
and-sticks, while two divalent zinc icons are shown as sol id spheres.
(From Manal lack DT, Hughes RA, Thompson PE. The next generation
of phosphodiesterase inhibitors: structural clues to l igand and
substrate selectivity of phosphodiesterases. J Med Chem
2005;48:3449–6342; with permission.) (See black and white image.)
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Fig. 17.7. Ribbon diagram of the active site of PDE4D2. The AMP
phosphate group binds two divalent zinc icons and forms hydrogen
bonds with His-160, Asp-201, and Asp-318. The adenine group of AMP
adopts an anticonformation and orients toward the hydrophobic pocket
made up of residues Tyr-159 (not shown), Leu-319, Asn-321, Thr-333,
Ile-336, Gln-369, and Phe-372. It forms three hydrogen bonds with
Gln-369 and Asn-321 and buttresses against Phe-372. The ribose of
AMP has a C3′-endo puckering configuration and makes van der
Waals contacts with residues His-160, Met-273, Asp-318, Leu-319,
Ile-336, Phe-340, and Phe-372. (From Manallack DT, Hughes RA,
Thompson PE. The next generation of phosphodiesterase inhibitors:
structural clues to l igand and substrate selectivity of
phosphodiesterases. J Med Chem 2005;48:3449–6342; with
permission.) (See black and white image.)
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Fig. 17.9. Overlay of sildenafil with 5′-GMP in the active site of PDE5.
(From Matot I, Gozal Y. Pulmonary responses to selective
phosphodiesterase-5 and phosphodiesterase-3 inhibitors. Chest
2004;125:644–651; with permission.) (See black and white image.)
Fig. 17.11. Overlay of (R,S)-rol ipram with 5′-AMP in the active site of
PDE4D. (From Maurice DH, Palmer D, Til ley DG, et al . Cycl ic
nucleotide phosphodiesterase activity, expression, and targeting in
cells of the cardiovascular system. Mol Pharmacol 2003;64:533–546;
with permission.) (See black and white image.)
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