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Structure-based optimization of 2,3-dioxopyrrolidines as potential inhibitors of flaviviral methyltransferases
Author :Prajakta Wangikar a, Elvis A. F. Martis a, Wahiba Aouadi b, Santosh R. Nandan *c, Etienne Decroly b and Evans C. Coutinho *a
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ABSTRACT
Various studies have shown that NS5 RNA methyltransferase (MTase) is a key enzyme involved in mRNA capping, a step crucial for flaviviral replication. Therefore, it has been identified as a potential target for therapeutic intervention in infections arising due to flaviviruses. In this paper, we report computer-assisted design of 2,3-dioxopyrrolidines, which were synthesized as guided by molecular docking studies on DENV and ZIKA MTase. Their chemical structures and geometric configuration were characterized by FT-IR, NMR (13C and 1H), MS and small molecule X-ray crystallography. Subsequently, their inhibitory potential was evaluated using an enzyme-based assay in DENV MTase (N7 and 2ʹO-MTase) and Zika virus MTase (N7 and 2ʹO-MTase). Furthermore, these molecules were also screened against RNMT (human N7 MTase). The most potent lead (compound W07) is seen to inhibit MTase from DENV with IC50 = 24.6±3.8 μM and ZIKA with IC50 = 9.0±1.7 μM. However, it also inhibits human N7 MTase, indicating plausible toxicity in humans. There is scope to further optimize these molecules to achieve selectivity towards flaviviral MTases.
KEYWORD
Flavivirus, methyltransferase, S-adenosyl-L-methionine, mRNA capping, 2,3-dioxopyrrolidines