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By analysing the physicochemical properties of a database of hits and leads, Keserü and Makara conclude that high-throughput screening, as well as hit-to-lead optimization practices in general, are responsible for the unfavourable physicochemical profile of recent leads and clinical candidates. Major adjustments may be needed to enable a balanced lead-evolution process and reduce the likelihood of high compound-related attrition in clinical trials.

Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.

Biomolecular condensates compartmentalize molecules without membranes. Understanding condensate composition is important given that their function relies on the selective exclusion or enrichment of molecules. Now, investigating small-molecule partitioning reveals variations across compounds, yet correlations indicate physical similarities between disparate condensates. Machine learning accurately predicts partitioning on the basis of physicochemical features, demonstrating the role of a hydrophobic environment in driving enrichment and exclusion.

Despite the wide acceptance of drug-like principles such as the 'rule of five', this analysis of molecules currently being synthesized in leading pharmaceutical companies reveals that their physical properties differ significantly from those of recently discovered oral drugs. The marked increase in lipophilicity in particular could increase the likelihood of attrition in drug development.

SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.

A machine learning model allows the identification of new small-molecule kinase inhibitors in days.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

Lucilia cuprina is a parasitic blowfly of major economic importance worldwide that feeds on the tissues of animals such as sheep. Here, the authors sequence the genome of L. cuprinaand provide insights into the fly’s molecular biology, interactions with the host animal and insecticide resistance.

The vast scale of emerging on-demand chemical collections presents a challenge for efficiently identifying promising drug candidates. Here, the authors develop a bottom-up computational strategy to first explore fragment space and then exploit the most promising scaffolds, successfully identifying diverse and potent BRD4 binders.

The cytochrome P450 enzyme CYP1B1 is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. Here the authors describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low-energy (660 nm) light.

The ageing brain retains the capacity for regeneration. This Review highlights the potential of the neurosteroid allopregnanolone as a regenerative therapeutic to promote self-renewal and repair in the brains of ageing individuals and those with Alzheimer disease. Windows of therapeutic opportunity for regeneration, and critical systems-biology factors that will determine the efficacy of regeneration are considered.

To advance our understanding of pathological features associated with Alzheimer’s disease (AD), chemical tools with distinct specificity towards AD targets would be valuable. Here the authors used a structure-mechanism-based design strategy to obtain small molecules as chemical regulators for distinct pathological factors linked to AD pathology.

Generating diverse structures with a minimum amount of synthetic effort is an important goal for drug discovery. Here, the authors report a two-phase synthesis for the generation of skeletally diverse small molecules—forming molecular scaffolds and subsequently diversifying each into multiple structures.

High-throughput screening and structure-guided design identified small-molecule inhibitors that prevent the interaction between N-terminally acetylated E2 conjugating enzyme UBE2M and DCN1, an E3 ligase for the ubiquitin-like protein Nedd8.

Several tuberculosis drugs are prodrugs that have to be enzymatically activated during metabolism. Ethionamide is such a drug and is activated by the monooxygenase EthA. EthA is itself regulated by the transcriptional repressor EthR. Here Alain Baulard and his colleagues have designed inhibitors of EthR that boost the antimycobacterial efficacy of ethionamide both in vitro and in vivo. Current therapy with ethionamide requires the use of high doses, often eliciting side effects. Its combination with the EthR repressor should allow lower doses to be used.

Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene synthase, an enzyme involved in cholesterol synthesis.

About 40% of human cancers carry missense mutations in the tumour suppressor protein p53. Here the authors identify a transiently open pocket in the protein, and by targeting a small molecule to it, partially restore mutant p53 tumour suppressor activity.

An automated approach designing drug ligands to multi-target profiles (with a 75% prediction success rate) is experimentally validated by the invention of novel ligands tailored to the complex and physiologically-relevant goal of identifying drugs that can specifically target profiles of multiple proteins.

The CMS Collaboration reports evidence for off-shell Higgs boson contributions in the production of Z boson pairs, and measures the width of the Higgs boson, which is inversely related to its lifetime.

Detailed computational and structural analysis of a large data set of non-peptidic macrocycles revealed particular functional groups, substituents and molecular properties that are critical for dictating cellular permeability.

In the past decade, the ability of nuclear magnetic resonance (NMR) spectroscopy to provide information on intermolecular interactions that is valuable in drug discovery has been increasingly appreciated. Pellecchia and colleagues provide their collective evaluation of the major applications of NMR in drug discovery, focusing on hit and lead generation, and critically analyse its current and potential utility.