Yu, Z. H. | bioRxiv Science

bioRxiv2026

Computational Design of Two Novel BRAF V600E Inhibitors: Exploiting Sulfoximine Bioisosterism and Chiral Constraints to Evade Paradoxical Activation

Metastatic melanoma is an aggressive cutaneous malignancy frequently driven by the oncogenic V600E mutation within the BRAF kinase. While first-generation Type IS BRAF inhibitors, such as dabrafenib, are currently prescribed to target this specific molecular vulnerability, paradoxical MAPK pathway activation, and acquired drug resistance necessitate the continuous development of structurally optimized lead molecules. In this study, chemical intuition, bioisosteric replacement, and computational molecular docking were employed to propose two novel BRAFV600E drug candidates. The proposed therapeutics, engineered to incorporate constrained sp3-hybridized aliphatic rings and a sulfoximine bioisostere, demonstrated thermodynamically superior docking scores within the mutant catalytic cleft compared to dabrafenib. Lastly, a homology analysis determined that Mus musculus is a suitable model organism for future preclinical studies and confirmed crucial structural selectivity against microbial off-target kinases.

pharmacology and toxicology↗

bioRxiv2019

Resilience to multiple stressors in an aquatic plant and its microbiome

PremiseEnvironments are changing rapidly, and outcomes of species interactions, especially mutualisms, are notoriously dependent on the environment. A growing number of studies have investigated responses of mutualisms to anthropogenic changes, yet most studies have focused on nutrient pollution or climate change, and tested single stressors. Relatively little is known about impacts of simultaneous chemical contaminants, which may differ fundamentally from nutrient or climate stressors, and are especially widespread in aquatic habitats.\n\nMethodsWe investigated the impacts of two common contaminants on interactions between the common duckweed Lemna minor and its microbiome. Sodium chloride (salt) and benzotriazole (a corrosion inhibitor) negatively affect aquatic organisms individually, yet commonly co-occur in runoff to duckweed-inhabited sites. We tested three L. minor genotypes with and without the culturable portion of their microbiome across field realistic gradients of salt (3 levels) and benzotriazole (4 levels) in a fully factorial experiment (72 treatments), and measured plant and microbial growth.\n\nKey ResultsWe found that stressors had conditional effects. Salt decreased both plant and microbial growth, but decreased plant survival more as benzotriazole concentrations increased. In contrast, benzotriazole did not affect microbial abundance, and benefited plants when salt and microbes were absent, perhaps due to the biotrans-formation we observed without salt. Microbes did not ameliorate duckweed stressors, as microbial inoculation increased plant growth, but not at high salt concentrations.\n\nConclusionsOur results suggest that multistressor effects matter when predicting responses of mutualisms to global change, but that mutualisms may not buffer organisms from stressors.

plant biology↗