Discovery of Small Molecule Inhibitors of PCSK9 Using Virtual Screening as Potential Therapeutics for Atherosclerosis
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Matthew N. Siciliano
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High LDL cholesterol can cause heart disease. Current treatments like statins are not always effective, so new therapies are needed. PCSK9 is a protein that reduces the number of LDL receptors in the liver, which keeps cholesterol in the blood, making it a strong target for new drugs. Blocking PCSK9 with small molecules could be a better alternative to current treatments. To find potential inhibitors, I first analyzed the PCSK9 protein to locate possible binding sites using computational methods, which revealed multiple sites that small molecules could target. Then, I created two pharmacophore maps and screened two chemical libraries to find molecules that fit the key interactions. I used molecular docking simulations to estimate how strongly these molecules bind to PCSK9, identifying several with strong predicted binding. Using SwissADME to check drug likeness and absorption properties, we narrowed down the candidates to seven molecules suitable for oral use. Finally, predicted toxicity was analyzed which helped identify the safest and most effective compounds. After comparing binding strength, drug likeness, and toxicity, Z73447142 and Z52103291 are the two most promising drug candidates for PCSK9. These molecules could be further tested using biophysical binding assays and cell-based experiments to confirm their effects, with the goal of eventually developing new oral treatments to lower cholesterol and reduce cardiovascular risk.
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Authors
Matthew N. Siciliano
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