131 research outputs found
Computationally Elucidating the Binding Kinetics for Different AChE Inhibitors to Access the Rationale for Improving the Drug Efficacy
Traditional drug discovery is based on a binding affinity
(thermodynamics)-driven
paradigm. Numerous examples, however, demonstrated that drug efficacy
does not always depend only on binding affinity but positively correlates
with binding kinetics, that is, the dissociation rate constant (koff). Binding free energy landscape (BFEL) constructor
is a computational binding kinetics prediction method, previously
developed by us, that estimates the binding kinetics for ligand-protein
based on their constructed binding free energy landscape, but it also
reveals the detailed molecular mechanism of the binding event, hence,
providing the position of transition states at the molecular level
to modify/improve the binding kinetics. Acetylcholinesterase (AChE)
is a well-known Alzheimer’s disease (AD) target for which there
is still not an ideal drug on the market. Therefore, to improve the
drug design strategy for AD, the binding kinetics and binding molecular
mechanisms of the four inhibitors of AChE, that is, E2020 (Aricept),
HupA, Rivastigmine, and Galantamine, were studied. Also, the differentiation
of the binding kinetics between mAChE and TcAChE was studied to evaluate the sensitiveness of BFEL
constructor. The flexibility of molecules has a noticeable effect
on the nature of BFEL. To the same target, flexible molecules (i.e.,
E2020 and Rivastigmine) which contain more rotatable bonds tend to
have more complicated BFELs reflecting more complicated molecular
action mechanisms than the rigid ones (i.e., HupA and Galantamine),
which therefore could be more challenging to be optimized. The binding
kinetics is highly dependent on the structure of the molecules, such
as the length and the functional groups. Therefore, E2020 presents
better binding kinetic and thermodynamic properties with either TcAChE or mAChE. Therefore, it is the most
promising lead drug for binding kinetics-based drug design. In addition,
the binding kinetics of a drug may present different values in the
proteins of different organisms because the residue compositions of
the binding gorges of the targets are variant, that is, E2020 shows
lower binding affinity and association energy barrier in binding with mAChE than TcAChE. However, HupA presents
a better binding property with TcAChE than mAChE
Rhodium(III)-Catalyzed Site-Selective C–H Alkylation and Arylation of Pyridones Using Organoboron Reagents
In this study we developed a method
for the pyridine-directed,
rhodium-catalyzed, site-selective C–H alkylation and arylation
of pyridones using commercially available trifluoroborate reagents.
This simple and versatile transformation proceeded smoothly under
relatively mild conditions with perfect site selectivity. The coupling
groups in the boron reagents can be extended to primary alkyl, benzyl,
and cycloalkyl. Moreover, direct C–H arylation products could
also be obtained under similar conditions
Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side
G protein-coupled
receptors (GPCRs) make up the largest family
of drug targets. The second extracellular loop (ECL2) and extracellular
end of the third transmembrane helix (TM3) are basic structural elements
of the GPCR ligand binding site. Currently, the disulfide bond between
the two conserved cysteines in the ECL2 and TM3 is considered to be
a basic GPCR structural feature. This disulfide bond has a significant
effect on receptor dynamics and ligand binding. Here, molecular dynamics
simulations and experimental results show that the two cysteines are
distant from one another in the highest-population conformational
state of ligand-free class A GPCRs and do not form a disulfide bond,
indicating that the dynamics of the GPCR extracellular side are different
from our conventional understanding. These surprising dynamics should
have important effects on the drug binding process. On the basis of
the two distinct ligand-free states, we suggest two kinetic processes
for binding of ligands to GPCRs. These results challenge our commonly
held beliefs regarding both GPCR structural features and ligand binding
Au(I)/Ag(I)-Catalyzed Cascade Approach for the Synthesis of Benzo[4,5]imidazo[1,2‑<i>c</i>]pyrrolo[1,2‑<i>a</i>]quinazolinones
An
efficient and facile AuÂ(I)/AgÂ(I)-catalyzed cascade method has
been developed for one-pot synthesis of the complex polycyclic heterocycles
benzoÂ[4,5]ÂimidazoÂ[1,2-<i>c</i>]ÂpyrroloÂ[1,2-<i>a</i>]Âquinazolinone derivatives through treatment of the substituted 2-(1<i>H</i>-benzoÂ[<i>d</i>]Âimidazol-2-yl)Âanilines with 4-pentynoic
acid or 5-hexynoic acid. The strategy features a AuÂ(I)/AgÂ(I)-catalyzed
one-pot cascade process involving the formation of three new C–N
bonds in high yields, and with broad a substrate scope
Au(I)/Ag(I)-Catalyzed Cascade Approach for the Synthesis of Benzo[4,5]imidazo[1,2‑<i>c</i>]pyrrolo[1,2‑<i>a</i>]quinazolinones
An
efficient and facile AuÂ(I)/AgÂ(I)-catalyzed cascade method has
been developed for one-pot synthesis of the complex polycyclic heterocycles
benzoÂ[4,5]ÂimidazoÂ[1,2-<i>c</i>]ÂpyrroloÂ[1,2-<i>a</i>]Âquinazolinone derivatives through treatment of the substituted 2-(1<i>H</i>-benzoÂ[<i>d</i>]Âimidazol-2-yl)Âanilines with 4-pentynoic
acid or 5-hexynoic acid. The strategy features a AuÂ(I)/AgÂ(I)-catalyzed
one-pot cascade process involving the formation of three new C–N
bonds in high yields, and with broad a substrate scope
Asymmetric One-Pot Sequential Mannich/Hydroamination Reaction by Organo- and Gold Catalysts: Synthesis of Spiro[pyrrolidin-3,2′-oxindole] Derivatives
An asymmetric organo- and gold-catalyzed one-pot sequential Mannich/hydroamination reaction has been developed. Using this protocol, spiro[pyrrolidin-3,2′-oxindole] derivatives were synthesized in good yields (up to 91%) and excellent enantioselectivities (up to 97% ee)
Interactions between UbcH5A (E2) and SUMO2 (sub) in the R2 trajectory.
<p>E2 UbcH5A is shown in cyan, E3 RNF4 is shown in green, Ub is shown in magenta, and substrate SUMO2 is shown in yellow. (A–C) Detail of interactions between E2 UbcH5A (cyan) and substrate SUMO2 (yellow). (D) Hydrogen bonds occupancies during production MD. (E) Hydrophobic interactions occupancies during production MD.</p
An Accurate Metalloprotein-Specific Scoring Function and Molecular Docking Program Devised by a Dynamic Sampling and Iteration Optimization Strategy
Metalloproteins,
particularly zinc metalloproteins, are promising
therapeutic targets, and recent efforts have focused on the identification
of potent and selective inhibitors of these proteins. However, the
ability of current drug discovery and design technologies, such as
molecular docking and molecular dynamics simulations, to probe metal–ligand
interactions remains limited because of their complicated coordination
geometries and rough treatment in current force fields. Herein we
introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific
docking program named MpSDock, which runs on a scheme similar to consensus
scoring consisting of a force-field-based scoring function and a knowledge-based
scoring function. For this purpose, in this study, an effective knowledge-based
zinc metalloprotein-specific scoring function based on the inverse
Boltzmann law was designed and optimized using a dynamic sampling
and iteration optimization strategy. This optimization strategy can
dynamically sample and regenerate decoy poses used in each iteration
step of refining the scoring function, thus dramatically improving
both the effectiveness of the exploration of the binding conformational
space and the sensitivity of the ranking of the native binding poses.
To validate the zinc metalloprotein-specific scoring function and
its special built-in docking program, denoted MpSDock<sub>Zn</sub>, an extensive comparison was performed against six universal, popular
docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4<sub>Zn</sub>, and EADock DSS. The zinc metalloprotein-specific knowledge-based
scoring function exhibited prominent performance in accurately describing
the geometries and interactions of the coordination bonds between
the zinc ions and chelating agents of the ligands. In addition, MpSDock<sub>Zn</sub> had a competitive ability to sample and identify native
binding poses with a higher success rate than the other six docking
programs
Mapping the Functional Binding Sites of Cholesterol in β<sub>2</sub>‑Adrenergic Receptor by Long-Time Molecular Dynamics Simulations
Cholesterol, an abundant membrane component in both lipid
rafts and caveolae of cell membrane, plays a crucial role in regulating
the function and organization of various G-protein coupled receptors
(GPCRs). However, the underlying mechanism for cholesterol-GPCR interaction
is still unclear. To this end, we performed a series of microsecond
molecular dynamics (MD) simulations on β<sub>2</sub>-adrenergic
receptor (β<sub>2</sub>AR) in the presence and absence of cholesterol
molecules in the POPC bilayer. The unbiased MD simulation on the system
with cholesterols reveals that cholesterol molecules can spontaneously
diffuse to seven sites on the β<sub>2</sub>AR surfaces, three
in the extracellular leaflet (e1–e3) and four in the intracellular
leaflet (i1, i2, i4, and i5). The MD simulation identifies three cholesterol-binding
sites (i2, e2, and e3) that are also observed in the crystal structures
of several GPCRs. Cholesterol binding to site e1 lock Trp313<sup>7.40</sup> into a certain conformation that may facilitate ligand–receptor
binding, and cholesterol binding to site i2 provides a structural
support for the reported cholesterol-mediate dimeric form of β<sub>2</sub>AR (PDB code 2RH1). In addition, both competitive and cooperative
effects between cholesterols and phospholipids in binding to β<sub>2</sub>AR were observed in our MD simulations. Together, these results
provide new insights into cholesterol–GPCR interactions
The proposed RING-catalyzed Ub transfer mechanism.
<p>The proposed RING-catalyzed Ub transfer mechanism.</p
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