Repurposing brucine as a chemopreventive agent in mammary gland carcinoma: Regulating lactate transport through MCT-4

In the present study, we aim to identify a potential drug candidate that targets the Monocarboxylate Transporter-4 (MCT-4) protein. Syrosingopine (SRY) is a well-established inhibitor of lactate transport through MCT-4. We screened 2,11,192 potential leads through ZINC database, which were atleast 50 % structurally similar with SYR. After in-depth analysis, 900 molecules were shortlisted based on Lipinski's rule, optimal molecular weight, binding energy, hydrogen bonding, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties that render them viable MCT-4 inhibitors. The outcome underscored Brucine (BRU) as the most promising lead molecule within a cohort of ten potential compounds. BRU is a monoterpenoid indole alkaloid and is used in the regulation of high blood pressure and other comparatively benign cardiac ailments. As such, no reports is available emphasizing the efficacy of BRU on lactate transport or mammary gland carcinoma. BRU demonstrated strong affinity for the MCT-4 transporter's catalytic domain, forming significant hydrophobic and polar interactions with essential amino acids at the binding site. BRU demonstrated significant cytotoxicity and increased the extracellular lactate levels in MCF-7 cells. The findings strongly encouraged BRU's effectiveness, offering promising paths for subsequent investigations. • The increasing prevalence of cancer poses significant challenges for medical professionals, necessitating the development of new treatments. • Brucine (BRU) stands out as the most promising candidate among ten potential compounds, showing strong affinity for the MCT-4 transporter. • BRU undergoes in-vitro analysis to assess its potential in breast cancer treatment, comparing its efficacy against established medications like SYR and Tamoxifen (TAM). • Various assays including MTT assay for cytotoxicity, lactate assay for MCT-4 inhibition, and comprehensive analyses involving nuclear condensation, mitochondrial membrane potential, and apoptotic alterations are conducted. • The findings strongly support the effectiveness of BRU, providing optimistic avenues for further research and development.