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[Bioorganic & Medicinal Chemistry] An integrated chemical biology approach reveals the mechanism


Abstract:

Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.

Nicholas Paganoa, 1, Peter Terietea, 1, Margrith E. Mattmanna, Li Yanga, Beth A. Snyderb, Zhaohui Caib, Marintha L. Heilb, Nicholas D.P. Cosforda, , a Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, United States b Southern Research Institute, Drug Development Division, 431 Aviation Way, Frederick, MD 21701, United States Received 23 December 2016, Revised 25 March 2017, Accepted 29 March 2017, Available online 8 April 2017 Show less https://doi.org/10.1016/j.bmc.2017.03.061

Link: http://www.sciencedirect.com/science/article/pii/S0968089617306570

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