Joong-Youn Shim, Ph.D. serves as the acting director of the Bioinformatics & Computational Chemistry Core of the EXPORT center. He completed his graduate work in the area of computational/organic chemistry & molecular modeling at the University of Georgia in 1994. His research interests encompass quantitative structure-activity relationships (QSAR) modeling, database mining, protein sequence alignment, protein homology modeling, protein fold recognition, protein/ligand and protein/protein docking, protein molecular dynamics (MD) simulations, molecular mechanism studies, and computer-aided drug design (CADD).
His current research projects include the molecular mechanism study of the human brain cannabinoid (CB1) receptor, a G-protein coupled receptor (GPCR), by applying the MD simulation approach to a molecular model of the CB1-G-protein complex embedded in a lipid bi-layer. His ultimate goal is to develop drugs targeting GPCRs based upon clear understanding of the ligand-induced GPCR activation, the initial key event in the whole G-protein signaling.
Cannabinoid Project
3D-QSAR studies of the cannabimimetic compounds (cannabinoids, AAIs, and anandamides) and the antagonist arylpyrazoles. To characterize
the shared pharmacophoric sites of interaction between cannabinoids, AAIs, anandamides, and arylpyrazole SR141716 analogs within the CB1 receptor
binding pocket, I applied the method of comparative molecular field analysis (CoMFA) to develop 3D-QSAR models that correlate variations in the
binding affinity with variations in the chemical structure.
a.
b.
c.
d.
The CoMFA models of cannabinoid compounds,
the united CoMFA model of cannabinoid and AAI compounds), the CoMFA model of anandamide analogs, and the CoMFA model of the arylpyrazole SR141716 analogs.
Homology model of the CB1 receptor, including the TM helical region and extracellular region in its inactive state.
I constructed a homology model of the CB1 receptor using the x-ray crystal structure of bovine rhodopsin as a template, guided by the highly
conserved amino acid residues at the TM helical region. Unlike most GPCRs, the CB1 receptor does not form the characteristic disulfide bridge between
TM3 and E2 due to the absence of a Cys residue in TM3. This CB1 receptor model was built such that a disulfide bridge exists between C(257) and C(264) in the E2 loop.
a.
b.
c.
d.
The CB1 receptor model
viewed from the membrane side (a) through (c) and from the extracellular side (d) showing E2 folded into the binding crevice. K3.28(192)
and E2 may be participating in ligand binding. Putative binding sites suggested from a binding site search are represented as white
dots (a). Superimposition of rhodopsin x-ray structure in purple with E2 in red and the CB1 receptor in green with E2 in cyan viewed
from the membrane side facing TM3 (b). The electrostatic potential map of the CB1 receptor surface rendered in blue (positive) and
red (negative) (c).TM1 through TM7 are colored in red, orange, yellow, green, cyan, blue, and purple, and the extracellular loops
are colored in magenta. Color coding of K3.28(192), C(257), and C(264): green, C; red, O; yellow, S; and white, H.
Docking of non-classical cannabinoid agonists, including AC-bicyclic CP47497 and CP55940, and ACD-tricyclic CP55244
at the binding site of the CB1 receptor. The binding conformations of non-classical cannabinoid agonists were identified by using the
molecular docking approach. We identified a hydrophobic pocket as the locus that has been proposed to interact with the C3 side chain of cannabinoids.
a.
b.
(a) Two alternative
docking conformations, C3-in (green) and C3-out (brown) of CP55244. TM helices 3 through 7 are colored in yellow, green, cyan, blue,
and purple. The extracellular loops are colored in magenta. All views are from the membrane side. (b) The hydrophobic pocket (brown)
of the CB1 receptor that interacts with the C3 side chain of CP55244 (ball and stick depiction).
Rotational energy barrier calculations for CP55244 and CP47497. As the first step in gaining insight into the molecular mechanisms
of the ligand-induced CB1 receptor conformational change, conformational properties of the non-classical cannabinoid CP55244 were characterized
by conformational analysis, rotational barrier calculations, and MD simulations. I proposed that the C3 side chain, as a steric trigger, of
CP55244 causes a steric clash in the receptor hydrophobic pocket and leading to receptor conformational changes.
MD simulations of CB1 receptor 4th intracellular loop (H8) in the 310- and α-helical conformations. An examination of the H8 sequence showed
that the extent of the 310-helical structural motif is associated with the positively charged amino acid residues that point toward the
intracellular side where the G-proteins exist and interact with the receptor. It was shown from MD simulations that the positively
charged residues of the N-terminal region of the 310- and α- forms of H8 formed sterically and electrostatically distinct clusters.
It is likely that this inter-conversion, by placing the positively charged side chains in specific places with a desirable orientation
for interacting with the negatively charged residues of the coupled G-proteins, would be able to dictate different signals to the G-proteins
or to turn on/off the signals.
a.
b.
(a) The electrostatic potential
map of H8 calculated by the Delphi] program. Connolly surface of H8 is rendered in blue and red to illustrate regions with electostatically
positive and negative, respectively, in the spectrum ranging from +5 to -5. (b) Isopotential map of H8 at the level of +2.0 kBT/e and -2.0 kBT/e.
For the αhelical conformation, the electrostatically positive and negative potential contours are displayed in cyan and magenta lines. For the
310-helical conformation, the electrostatically positive and negative potential contours are displayed in blue and red polyhedra.
Students interested in working with Dr. Shim may contact him directly.
Howlett, A. C., Padgett, L. W., and Shim, J.-Y. Cannabinoid Agonist-selective Regulation of G-protein Coupling. In: The Cannabinoid Receptors; P.H. Reggio, Ed., Humana Press, 2008, 173-193.
