Transport mechanism and drug discovery of human monocarboxylate transporter 1

Human monocarboxylate transporters (MCTs) are crucial for tumour cell glycolysis. Inhibiting MCT-mediated lactate transport can suppress the proliferation of solid tumours and enhance the efficacy of the immune system against tumours. Despite the importance of this transporter, the molecular mechanism of lactate transport by MCT1 remains elusive, hindering the development of targeted therapies. Here, we used principal component analysis to elucidate the allosteric mechanisms of the MCT family. Enhanced sampling revealed that specific residue pairs (E46-K289 and E376-R143) are essential for maintaining the inwards and outwards conformations of MCT1. Quantum chemical calculations and umbrella sampling demonstrated that lactate molecules and protons are co-transported sequentially, with K38 and R313 playing key roles in lactate translocation. On the basis of these data, we conducted a drug screening campaign targeting the core pocket of MCT1 and identified silybin as a selective MCT1 inhibitor. Silybin had significant inhibitory effects on tumour cells with high MCT1 expression. These findings provide a comprehensive understanding of the lactate transport mechanism of MCT1 and lay the groundwork for the rational design of antitumour drugs targeting MCT1.