Chem最新文献

G protein-coupled receptors (GPCRs) are membrane proteins targeted by over one-third of marketed drugs. Understanding their activation mechanism is essential for precise regulation of drug pharmacological response. In this work, we elucidate the conformational landscape of the adenosine A_2A receptor (A_2AR) activation mechanism in its basal apo form and under different ligand-bound conditions through minute-timescale free-energy calculations. We identified a pseudo-active state (pAs) of the A_2AR apo form, stabilized by specific “microswitch” residues, including a salt bridge established between the conserved residues R^5.66 and E^6.30. The pAs enables A_2AR to couple with Gs protein upon rearrangement of the intracellular end of transmembrane helix 6, providing unprecedented structural insights into receptor function and signaling dynamics. Our simulation protocol is versatile and can be adapted to study the activation of any GPCRs, potentially making it a valuable tool for drug design and “biased signaling” studies.

Understanding how a macromolecule’s primary sequence governs its conformational landscape is crucial for elucidating its function, yet these design principles are still emerging for macromolecules with intrinsic disorder. Herein, we introduce a high-throughput workflow that implements a practical colorimetric conformational assay, introduces a semi-automated sequencing protocol using matrix-assisted laser desorption/ionization and tandem mass spectrometry (MALDI-MS/MS), and develops a generalizable sequence-structure algorithm. Using a model system of 20mer peptidomimetics containing polar glycine and hydrophobic N-butylglycine residues, we identified nine classifications of conformational disorder and isolated 122 unique sequences across varied compositions and conformations. Conformational distributions of three compositionally identical library sequences were corroborated through atomistic simulations and ion mobility spectrometry coupled with liquid chromatography. A data-driven strategy was developed using existing sequence variables and data-derived “motifs” to inform a machine-learning algorithm toward conformation prediction. This multifaceted approach enhances our understanding of sequence-conformation relationships and offers a powerful tool for accelerating the discovery of materials with conformational control.

Alkynes have played pivotal roles in numerous synthetic transformations and materials science. Here, by developing nitrogen-deletion coupling, we describe a modular synthesis of alkynes from widely accessible nitriles by swapping the N atom to a C atom in cyano groups, where lithiated gem-diborylalkanes and tert-butyl nitrite are applied sequentially. NMR analysis and crystal structure show the nature of an intermediary α-boryl lithium enamine. A diverse range of nitriles are converted into various internal and terminal alkynes within a short reaction time, including alkynes bearing bulky secondary and tertiary alkyl substituents on both sides.

β-Lactams are privileged and appealing motifs in medicinal chemistry. Herein, we report enantioselective desymmetrization and parallel kinetic resolution of aminocyclopropanes for the synthesis of chiral β-lactams through Rh(I)-catalyzed asymmetric C–C bond activation. The chiral Rh(I) catalyzed C–C bond cleavage of aminocyclopropanes first and then underwent β-hydride elimination to generate π-allylic hydridorhodium(III) intermediates, which could be trapped by tethered alkyne units, and gave various strained chiral β-lactams with excellent regio- and enantioselectivity (90%–99% ee). Moreover, parallel kinetic resolution was realized when using unsymmetrical aminocyclopropanes with pre-existing C2-stereocenters through C–C bond activation, delivering two types of β-lactams in one pot with excellent enantiomeric excesses. Notably, these systems achieve complete atom and step economy. The obtained enantioenriched β-lactams exhibit the capability to undergo a variety of stereospecific transformations. Theoretical calculations reveal the origin of enantioselectivity and support the alkyne unit insertion to allylic Rh(III) –C bond mechanisms.

Natural products have historically represented a major source of therapeutics and small-molecule probes for interrogating biological systems. Here, we describe the design and implementation of P450-mediated chemoenzymatic diversity-oriented synthesis (CeDOS), a strategy in which selective, regiodivergent P450-catalyzed oxyfunctionalizations are leveraged as key steps for enabling the skeletal rearrangement and diversification of a parent compound. Using this strategy and plant-derived parthenolide as the parent molecule, a structurally diverse library of over 50 unprecedented natural-product-like scaffolds was generated via divergent chemoenzymatic routes. Importantly, several members of this CeDOS library were found to exhibit notable cytotoxicity against human cancer cells as well as diversified anticancer activity profiles. This work demonstrates the power of CeDOS as a strategy for directing the construction and discovery of novel bioactive molecules, and it offers a blueprint for the broader application of this approach toward the creation and exploration of natural-product-like chemical libraries.