Binding Lumateperone with Cucurbit[8]uril to Improve Drug Bioavailability
Abstract
The purpose of this study is to improve the bioavailability of the atypical antipsychotic, lumateperone, which is currently used to treat schizophrenia. Lumateperone has a bioavailability of 4.4%. Increasing the bioavailability would allow the drug to be administered in lower doses, reducing production cost and side-effects of the drug. We determined that the best method for improving the bioavailability of lumateperone is to pair it with a drug carrier, which is a host molecule that potentially protects the molecule from first-pass metabolism and aids in the release of the compound into systemic circulation. We selected a handful of drug carriers, and performed docking calculations with the ligand, lumateperone. Cucurbit[8]uril (CB8) had the highest binding affinity, so we continued to run more tests on the drug carrier. Molecular dynamics simulations showed an increase in polar interactions with water from -20.2 kcal/mol for the ligand to -57.2 kcal/mol for the ligand-host system. Nonpolar interactions with water increased from -29.4 kcal/mol for the ligand to -65.6 kcal/mol for the ligand-host system. Pairing lumateperone with CB8 yielded a significant enhancement of the molecule’s polar and nonpolar interactions with water. The molecular dynamics simulations also demonstrated the stability of the host-ligand dynamics. The favorable molecular dynamics energies along with the promising stability of the host-ligand system suggests that pairing lumateperone with CB8 improves the solubility, and therefore the bioavailability, of the drug.
Binding Lumateperone with Cucurbit[8]uril to Improve Drug Bioavailability
HSS 202
The purpose of this study is to improve the bioavailability of the atypical antipsychotic, lumateperone, which is currently used to treat schizophrenia. Lumateperone has a bioavailability of 4.4%. Increasing the bioavailability would allow the drug to be administered in lower doses, reducing production cost and side-effects of the drug. We determined that the best method for improving the bioavailability of lumateperone is to pair it with a drug carrier, which is a host molecule that potentially protects the molecule from first-pass metabolism and aids in the release of the compound into systemic circulation. We selected a handful of drug carriers, and performed docking calculations with the ligand, lumateperone. Cucurbit[8]uril (CB8) had the highest binding affinity, so we continued to run more tests on the drug carrier. Molecular dynamics simulations showed an increase in polar interactions with water from -20.2 kcal/mol for the ligand to -57.2 kcal/mol for the ligand-host system. Nonpolar interactions with water increased from -29.4 kcal/mol for the ligand to -65.6 kcal/mol for the ligand-host system. Pairing lumateperone with CB8 yielded a significant enhancement of the molecule’s polar and nonpolar interactions with water. The molecular dynamics simulations also demonstrated the stability of the host-ligand dynamics. The favorable molecular dynamics energies along with the promising stability of the host-ligand system suggests that pairing lumateperone with CB8 improves the solubility, and therefore the bioavailability, of the drug.
