The library was screened against crystals of a crystallographically optimized HIV-1 RT variant (RT52A) in complex with the NNRTI inhibitor rilpirivine (RPV). The screening library consisted of 775 commercially available compounds that were grouped into 143 cocktails. reported an X-ray crystallographic fragment screen targeted towards HIV-1 RT. In FBDD, libraries of low molecular weight chemical compounds, typically 300 Da or less, are screened using biophysical methods for binding to the protein target, with the notion that smaller molecules can make efficient binding interactions. FBDD aims to develop small molecule drugs with good pharmaceutical properties starting with chemical building blocks of drugs that are subsequently elaborated into larger more potent inhibitors. One relatively recent approach to discovering new druggable sites and compounds is fragment-based drug discovery (FBDD). Although these two classes of drugs are effective for HIV-1 treatment and prevention, continued efforts to minimize drug resistance and side effects associated with lifelong antiretroviral therapy are desirable by identification of new druggable sites on RT and continued development of new compounds. NNRTIs bind to a site that is proximal but distinct from the active site and act by an allosteric inhibition mechanism, locking RT into a non-active state. NRTIs are analogues of the natural dNTP substrate and bind to the active site of RT. RT inhibitors belong to two major classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Food and Drug Administration approved antiretroviral therapies target this enzyme. RT is an important target for anti-HIV drugs, and nearly 50% of U.S. HIV-1 reverse transcriptase (RT) is a virally encoded enzyme that transcribes the viral RNA genome into a proviral DNA precursor prior to integration into the host genome. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host’s immune system leading to acquired immunodeficiency syndrome and potentially death.
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