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The process of developing new drugs is arduous and costly, particularly for targets classified as "difficult-to-drug." Macrocycles show a particular ability to modulate difficult-to-drug targets, including protein-protein interactions, while still allowing oral administration. However, the determination of membrane permeability, critical for reaching intracellular targets and for oral bioavailability, is laborious and expensive. In silico methods are a cost-effective alternative, enabling predictions prior to compound synthesis. Here, we present a comprehensive online database (https://swemacrocycledb.com/), housing 5638 membrane permeability datapoints for 4216 nonpeptidic macrocycles, curated from the literature, patents, and bioactivity repositories. In addition, we present a new descriptor, the "amide ratio" (AR), that quantifies the peptidic nature of macrocyclic compounds, enabling the classification of peptidic, semipeptidic, and nonpeptidic macrocycles. Overall, this resource fills a gap among existing databases, offering valuable insights into the membrane permeability of nonpeptidic and semipeptidic macrocycles, and facilitating predictions for drug discovery projects. [ABSTRACT FROM AUTHOR]

Cholesky decomposition (CD) of the two-electron integrals and the resolution-of-identity (RI) techniques are established inner projection methods to efficiently evaluate two-electron integrals. Both approaches share the notion of an auxiliary basis set as a mean to reduce the scaling. In the past years, the close relationship between the two approaches has fostered developments on how to systematically derive unbiased auxiliary basis sets – atomic CD (aCD) and atomic compact CD (acCD) auxiliary basis sets, different to the precomputed auxiliary basis sets. The accuracy of these approximations in the RI approach can be further improved via an explicit correction of the one-centred two-electron integrals, which is the main object of this research. Correcting the one-centred two-electron integrals directly, which scales linear with system size, is expected to provide a new degree of freedom to the design of auxiliary basis sets. This can either be used to gain faster convergence towards the conventional treatment of the two-electron integrals or as a mean to design lighter auxiliary basis sets while maintaining the same accuracy as of the uncorrected approach. The benchmarks of the one-centre corrections applied to several auxiliary basis set types were investigated in this paper. [ABSTRACT FROM AUTHOR]

Recently, mechanical ball milling was applied to chitin depolymerization. The mechanical activation afforded higher selectivity toward glycosidic bond cleavage over amide bond breakage. Hence, the bioactive N -acetylglucosamine (GlcNAc) monomer was preferentially produced over glucosamine. In this regard, the force-dependent mechanochemical activation-deactivation process in the relaxed and pulled GlcNAc dimer undergoing deacetylation and depolymerization reactions was studied. For the relaxed case, the activation energies of the rate-determining steps (RDS) proved that the two reactions could occur simultaneously. Mechanical forces associated with ball milling were approximated with linear pulling and were introduced explicitly in the RDS of both reactions through force-modified potential energy surface (FMPES) formalism. In general, as the applied pulling force increases, the activation energy of the RDS of deacetylation shows no meaningful change, while that of depolymerization decreases. This result is consistent with the selectivity exhibited in the experiment. Energy and structural analyses for the depolymerization showed that the activation can be attributed to a significant change in the glycosidic dihedral at the reactant state. A lone pair of the neighboring pyranose ring O adopts a syn -periplanar conformation relative to the glycosidic bond. This promotes electron donation to the σ*-orbital of the glycosidic bond, leading to activation. Consequently, the Brønsted-Lowry basicity of the glycosidic oxygen also increases, which can facilitate acid catalysis.