Project Summary: The goal of this research proposal is to understand the molecular basis of blocking bitter taste for HIV/AIDS drugs so that their often unpleasant bitter taste can be eliminated. Some drugs have a strong bitter taste, which makes it a challenging task for patients to take them, especially for infants and young children. Because many children cannot swallow pills, pediatric medicines usually come in liquid or syrup form, which frequently taste bitter and is very difficult to mask, even in flavored liquid formulations. It has been reported that when children refuse to take the bitter-tasting HIV/AIDS drugs, and do not get the proper dosage of their drugs, they can develop resistance to the drugs, which has serious consequences for their health. Therefore, there is a need to develop bitter taste blockers to mask the unpleasant taste of HIV/AIDS drugs. Understanding the mechanism of bitter-tasting drug-induced TAS2R receptor activation is likely to lead to discovering bitter taste blockers, which could be used to mask the unpleasant taste of HIV/AIDS drugs. In this proposal, we have developed testable models of the HIV/AIDS drug- TAS2R receptors by computational approaches and our plan is to test them experimentally. Moreover, using structure-based drug design and organic synthesis we aim to discover novel human TAS2R specific blockers to mask the unpleasant bitter taste of different HIV/AIDS drugs.