Ab Initio Study of Hydrostable Metal-Organic Frameworks for Postsynthetic Modification and Tuning toward Practical Applications.

Metal-organic frameworks (MOFs), a subclass of nanoporous coordination polymers, have emerged as one of the most promising next-generation materials. The postsynthetic modification method, a strategy that provides tunability and control of these materials, plays an important role in enhancing its properties and functionalities. However, knowing adjustments which leads to a desired structure-function a priori remains a challenge. In this comprehensive study, the intermolecular interactions between 21 industrially important gases and a hydrostable STAM-17-OEt MOF were investigated using density functional theory. Substitutions on its 5-ethoxy isophthalate linker included two classes of chemical groups, electron-donating (-NH2, -OH, and -CH3) and electron-withdrawing (-CN, -COOH, and -F), as well as the effect of mono-, di-, and tri-substitutions. This resulted in 651 unique MOF-gas complexes. The adsorption energies at the ground state and room temperature, bond lengths, adsorption geometry, natural bond orbital analysis of the electric structure, HOMO-LUMO interactions, and the predicted zwitterionic properties are presented and discussed. This study provides a viable strategy for the functionalization, which leads to the strongest affinity for each gas, an insight into the role of different chemical groups in adsorbing various gas molecules, and identifies synthetic routes for moderating the gas adsorption capacity and reducing water adsorption. Recommendations for various applications are discussed. A custom Python script to assess and visualize the hypothetical separation of two equal gas mixtures of interest is provided. The methodology presented here provides new opportunities to expand the chemical space and physical properties of STAM-17-OEt and advances the development of other hydrostable MOFs.

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery.

Macrocyclic peptides (MCPs) are an emerging class of promising drug modalities that can be used to interrogate hard-to-drug ("undruggable") targets. However, their poor intestinal stability is one of the major liabilities or obstacles for oral drug delivery. We therefore investigated the metabolic stability and biotransformation of MCPs via a systematic approach and established an integrated in vitro assay strategy to facilitate MCP drug discovery, with a focus on oral delivery liabilities. A group of diverse MCPs were incubated with representative matrices, including simulated intestinal fluid with pancreatin (SIFP), human enterocytes, liver S9 fractions, liver lysosomes, plasma, and recombinant enzymes. The results revealed that the stability and biotransformation of MCPs varied, with the major metabolic pathways identified in different matrices. Under the given conditions, the selected MCPs generally showed better stability in plasma compared to that in SIFP. Our data suggest that pancreatic enzymes act as the primary metabolic barrier for the oral delivery of MCPs, mainly through hydrolysis of their backbone amide bonds. Whereas in enterocytes, multiple metabolic pathways appeared to be involved and resulted in metabolic reactions such as oxidation and reduction in addition to hydrolysis. Further studies suggested that lysosomal peptidase cathepsin B could be a major enzyme responsible for the cleavage of side-chain amide bonds in lysosomes. Collectively, we developed and implemented an integrated assay for assessing the metabolic stability and biotransformation of MCPs for compound screening in the discovery stage toward oral delivery. The proposed question-driven assay cascade can provide biotransformation insights that help to guide and facilitate lead candidate selection and optimization.