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 Au­(I)/Ag­(I)-catalyzed cascade method has been developed for one-pot synthesis of the complex polycyclic heterocycles benzo­[4,5]­imidazo­[1,2-<i>c</i>]­pyrrolo­[1,2-<i>a</i>]­quinazolinone derivatives through treatment of the substituted 2-(1<i>H</i>-benzo­[<i>d</i>]­imidazol-2-yl)­anilines with 4-pentynoic acid or 5-hexynoic acid. The strategy features a Au­(I)/Ag­(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 Au­(I)/Ag­(I)-catalyzed cascade method has been developed for one-pot synthesis of the complex polycyclic heterocycles benzo­[4,5]­imidazo­[1,2-<i>c</i>]­pyrrolo­[1,2-<i>a</i>]­quinazolinone derivatives through treatment of the substituted 2-(1<i>H</i>-benzo­[<i>d</i>]­imidazol-2-yl)­anilines with 4-pentynoic acid or 5-hexynoic acid. The strategy features a Au­(I)/Ag­(I)-catalyzed one-pot cascade process involving the formation of three new C–N bonds in high yields, and with broad a substrate scope

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_Zn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4_Zn, 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_Zn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs

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)

Mapping the Functional Binding Sites of Cholesterol in β₂‑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 β₂-adrenergic receptor (β₂AR) 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 β₂AR 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 Trp313^7.40 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 β₂AR (PDB code 2RH1). In addition, both competitive and cooperative effects between cholesterols and phospholipids in binding to β₂AR 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