Discovery of Small Molecules Targeting Mer-TK as Novel Therapies for Cardiovascular Diseases
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Aditya Sharma
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Cardiovascular diseases remain the leading cause of death worldwide. Currently, FDA-approved therapies primarily manage cholesterol, blood pressure, and clot formation without correcting the underlying issues in apoptotic cell clearance that drive plaque instability and chronic inflammation. MER proto-oncogene tyrosine kinase (MerTK), a receptor central to efferocytosis, has emerged as a promising target for addressing this gap, yet no MerTK-targeted small molecule therapy currently exists for cardiovascular disease. This study used a structure-based computational pipeline to identify and evaluate candidate small molecules targeting MerTK. First, the MerTK structure was analyzed using ProteinsPlus and PrankWeb to identify its most druggable binding pocket, revealing a single dominant site with a drug score of 0.82-0.83. Second, a pharmacophore model built from this pocket was used to virtually screen compound libraries, yielding fifteen candidates with strong geometric alignment (RMSD ≤ 0.127 Å). Third, molecular docking of these fifteen compounds against the binding pocket produced SwissParam scores ranging from -6.85 to -8.83 kcal/mol, narrowing the pool to eight top binders. Fourth, ADME and Lipinski’s Rule screening of these eight compounds identified four candidates with favorable absorption, solubility, and drug-likeness profiles. Fifth, toxicity prediction of these four finalists evaluated lethal dose, toxicity class, and toxicological endpoint breadth. Together, these results identified MolPort-047-786-433 as the most promising overall candidate, combining strong predicted binding affinity (-8.2918 kcal/mol), full Lipinski compliance, high gastrointestinal absorption, and the most favorable toxicity profile (LD50 of 1190 mg/kg, toxicity class 4) among all candidates screened.
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Authors
Aditya Sharma
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References:
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