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Repurposing brucine as a chemopreventive agent in mammary gland carcinoma: Regulating lactate transport through MCT-4
Asma Khatoon Zaidi1, Anurag Kumar1, Rohit Kumar1
1Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India.
Abstract:
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.
Insights
Researchers identified Brucine (BRU) as a promising drug candidate targeting Monocarboxylate Transporter-4 (MCT-4). This compound effectively inhibits lactate transport and shows cytotoxicity in cancer cells, suggesting potential therapeutic applications.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Monocarboxylate Transporter-4 (MCT-4) plays a crucial role in lactate transport.
- Inhibiting MCT-4 is a potential therapeutic strategy for certain cancers.
- Syrosingopine (SRY) is a known MCT-4 inhibitor, serving as a reference compound.
Purpose of the Study:
- To identify novel drug candidates targeting the Monocarboxylate Transporter-4 (MCT-4) protein.
- To evaluate the potential of lead compounds as inhibitors of lactate transport.
- To assess the efficacy of identified compounds in cancer cell lines.
Main Methods:
- Screened over 211,000 compounds from the ZINC database for structural similarity to Syrosingopine (SRY).
- Shortlisted 900 molecules based on Lipinski's rule, molecular weight, binding energy, hydrogen bonding, and ADMET properties.
- Evaluated the binding affinity, cytotoxicity, and effect on extracellular lactate levels of lead compounds in MCF-7 cells.
Main Results:
- Brucine (BRU) emerged as the most promising lead compound among the top ten candidates.
- BRU exhibited strong binding affinity to the MCT-4 catalytic domain through hydrophobic and polar interactions.
- BRU demonstrated significant cytotoxicity and increased extracellular lactate levels in MCF-7 cells.
Conclusions:
- Brucine (BRU) is a potent inhibitor of Monocarboxylate Transporter-4 (MCT-4).
- BRU shows significant potential as a therapeutic agent for targeting lactate transport in cancer.
- Further investigations into BRU's efficacy against mammary gland carcinoma are warranted.
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