Friday, March 11, 2022

Identification and In Silico Binding Study of a Highly Potent DENV NS2B-NS3 Covalent Inhibitor

Xincheng Lin, Jiawei Cheng, Yuming Wu, Yaoliang Zhang, Hailun Jiang, Jian Wang, Xuejun Wang, and Maosheng Cheng

ACS Medicinal Chemistry Letters  2022

DOI: 10.1021/acsmedchemlett.1c00653

Dengue virus (DENV), an arthropod-borne flavivirus, has developed rapidly in the past few decades and becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of viral proteins makes it the most promising target for anti-DENV drug discovery. In the current work, a potent NS2B-NS3 covalent inhibitor 23 (IC50 = 6.0 nM, kinac/Ki = 1581 M–1 s–1) was discovered through the chemical modification of a published covalent inhibitor 1 (IC50 = 500 nM, kinac/Ki = 156.1 M–1 s–1), followed by in vitro assay. Further comprehensive structure–activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...