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Medicinal chemistry deals with the design, optimization and development of chemical compounds for use as drugs. It is inherently a multidisciplinary topic — beginning with the synthesis of potential drugs followed by studies investigating their interactions with biological targets to understand the medicinal effects of the drug, its metabolism and side-effects.
Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.
Parkin is a ubiquitin ligase that protects against early-onset Parkinson’s disease. Here, the authors show a molecular glue that promotes binding of phosphorylated ubiquitin to parkin and rescues the mitophagy defect of mutations in the parkin ubiquitin-like domain.
In this work, the authors probe the efficacy of BWC0977, a bacterial topoisomerase inhibitor, in pre-clinical animal models, also demonstrating that BWC0977 is safe and well tolerated in healthy human volunteers, in a phase 1 trial.
Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is challenging because of the enzyme’s shallow catalytic pocket and non-specific substrate binding interactions. Here, the authors use Sulfur (VI) fluoride exchange chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with the Y204 residue that position DNA.
Chemical language models are deep learning models trained with molecules in string representation. They enable data-driven de novo design of molecules with tailored features. Here, the authors used chemical language models to design multi-target ligands.
Inhibiting a signal transducer, which kicks off the production of β-lactamase in response to the presence of an antibiotic, shuts down resistance and makes β-lactam antibiotics effective once more.
Orally bioavailable, high molecular weight macrocyclic peptides that inhibit difficult-to-drug protein–protein interactions are of high therapeutic value, and rules for their design were proposed recently. Here, we emphasize the danger of rules that provide a false impression of the lipophilicity required of a clinical candidate.