Biomedical Engineering Reference
In-Depth Information
In the absence of a three-dimensional structure of nicotinic acetylcholine recep-
tor (nAChR), crystal structures of acetylcholine binding protein (AChBP) from
three species of sea snails:
Lymnaea stagnalis
(Ls);
Aplysia californica
(Ac); and
Bulinus truncates
(Bt) were used instead. Ligands from the National Cancer
Institute Diversity Set (NCIDS) were docked into three species of AChBP using
relaxed-complex method, which involved MD simulations and docking. These
yielded 15 different conformations of the AChBP. Most ligands were found to
bind behind the C-loop between two subunits. Novel blockers with significant
potential were identified either for the common binding to all receptor confor-
mations or were shown to selectively bind to specific receptor conformations [
49
].
Screening agonists against
a
7-nAChR using a combination of docking and MD
simulations, and in conjunction with an analysis of hydrophobic/hydrophilic inter-
actions, yielded seven compounds as possible leads for Alzheimer's disease
therapy: gx-50, gx-51, gx-52, gx-180, open3d-99008, open3d-51265, open3d-
60247 [
58
].
Sixteen agonists with known activity for homomeric
7 channels of nAChR
were used to validate a simplified combination of docking, cluster analysis, and
MM-PBSA method. Using the relative binding free energy from the structurally
different compounds in test set, morpholine-containing compounds did not appear
to improve the affinity at the
a
7-nAChRs while two novels structurally related
analogues were predicted to have a high affinity for
a
7 subtype and were subse-
quently assayed in binding experiments [
59
]. A ligand-based virtual screening
approach can also be useful to obtain novel blockers. ATP-sensitive potassium
channels (K
ATP
channels) are a target in the treatment of diabetes, where potassium
channel openers (KCOs) such as the yanoguanidines, benzopyrans, and 1,2,4-
thiadiazines stimulate potassium currents. 65,208 compounds were carefully
assessed for chirality, protonation state, and tautomerism was filtered using the
VolSurf procedure, which are descriptors related to the GRIND, FLAP, and TOPP
approaches. While final 32 hits found, the top-ranked ligands from each methods
could be different. Carosati and co-worker suggested that parallel application
needed to enhance the probability of finding novel KCOs [
48
].
a
3 MD Simulations of Ion Channels Blockers
An MD simulation is a theoretical method to assess dynamic aspects associated
with molecular systems. Whilst changing of the molecular coordinate is determined
by motions including translation, rotation and vibration causing by atomic
interactions, the energy function is the key factors driven atomic movement [
60
].
Several energy functions are available through simulation packages such as
AMBER, CHARMM, Gromacs and Tripos force field. Therefore, the particular
dynamics of a system like ease of and type of conformational changes as well as
thermodynamic properties can be obtained from MD simulations making this
technique popular for the biomolecule systems [
61
]. In this section, we discuss
