GPCRLigNet: rapid screening for GPCR active ligands using machine learning.

Molecules with bioactivity towards G protein-coupled receptors represent a subset of the vast space of small drug-like molecules. Here, we compare machine learning models, including dilated graph convolutional networks, that conduct binary classification to quickly identify molecules with activity towards G protein-coupled receptors. The models are trained and validated using a large set of over 600,000 active, inactive, and decoy compounds.

Helical Molecular Springs with Varying Spring Constants.

We report a general synthetic route toward helical ladder polymers with varying spring constants, built with chirality-assisted synthesis (CAS). Under tension and compression, these shape-persistent structures do not unfold, but rather stretch and compress akin classical Hookean springs. Our synthesis is adaptable to helices with different pitch and diameter, which allowed us to investigate how molecular flexibility in solution depends on the exact geometry of the ladder polymers.

A computational study of cooperative binding to multiple SARS-CoV-2 proteins.

Structure-based drug design targeting the SARS-CoV-2 virus has been greatly facilitated by available virus-related protein structures. However, there is an urgent need for effective, safe small-molecule drugs to control the spread of the virus and variants. While many efforts are devoted to searching for compounds that selectively target individual proteins, we investigated the potential interactions between eight proteins related to SARS-CoV-2 and more than 600 compounds from a traditional Chinese medicine which has proven effective at treating the viral infection.

Enhanced sampling protocol to elucidate fusion peptide opening of SARS-CoV-2 spike protein.

Large-scale conformational transitions in the spike protein S2 domain are required during host-cell infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes because of the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a dynamic selection algorithm, and Markov state models to interrogate the structural changes of the S2 domain.

Iterative Exponential Growth of Oxygen-Linked Aromatic Polymers Driven by Nucleophilic Aromatic Substitution Reactions.

This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (SAr) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) H-H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C-H bonds of the electron-poor pyrimidine functions.

Size-selective Catalytic Polymer Acylation with a Molecular Tetrahedron.

Selective catalysis at the molecular level represents a cornerstone of chemical synthesis. However, it still remains an open question how to elevate tunable catalysis to larger length scales to functionalize whole polymer chains in a selective manner. We now report a hydrazone-linked tetrahedron with wide openings, which acts as a catalyst to size-selectively functionalize polydisperse polymer mixtures.

MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria.

Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans.