Pakistan-US Science and Technology Cooperation Program  Phase 6 (2015 Deadline) Novel Compounds by Structural Modifications of Anti-HIV Drug (Delavirdine) and their Antiviral Screening US partner: Raymond Schinazi, Emory University (No funding requested on the U.S. side) Pak partner: Sana Aslam, Government College for Women University, Faisalabad Progress Reports 2016: The premise of our project is that structural modifications of the potent anti-HIV drug, Delavirdine mesylate, may result in enhancement of antiviral activity. Our systematic approach uses molecular docking of representative compounds from this family against the NNRTI binding pocket of the HIV reverse transcriptase (RT) enzyme to predict/select potential modifications from a library of related compounds. To date, we have synthesized over 40 molecular analog compounds and screened them for anti-HIV-1activity and cytotoxicity. Three compounds (HLS-961, HLS-962 and HLS-963) were found to have approximate activities (EC50) in human peripheral blood mononuclear cells (PBM) cells of <10 μM and marginal or no cytotoxicity (IC50 > 50 μM) in CEM, Vero or PBM cells. Further characterization of these promising compounds including dose response studies are currently underway. 2017: The premise of our project is that structural modifications of the potent anti-HIV drug, Delavirdine mesylate, may result in enhancement of antiviral activity. Our systematic approach uses molecular docking of representative compounds from this family against NNRTI binding pocket of HIV RT enzyme to predict/select potential modifications from a library of related compounds. To date, we have subsequently synthesized 43 molecular analogs and evaluated them for anti-HIV-1 activity and cytotoxicity. Three compounds (HLS-961, HLS-962 and HLS-963) on initial screening were found to have approximate activities (EC50) in human PBM cells of <10 μM that were not reproducible upon further studies. Data results found inconsistency associated with limited solubility in DMSO. Further studies are underway to improve solubility/stability issues using 20% DMSO, 50% PEG-400 and 30% phosphate buffered saline.