title: Discovery and SAR studies of methionine-proline anilides as dengue virus NS2B-NS3 protease inhibitors.
abstract: A series of methionine-proline dipeptide derivatives and their analogues were designed, synthesized and assayed against the serotype 2 dengue virus NS2B-NS3 protease, and methionine-proline anilides 1 and 2 were found to be the most active DENV 2 NS2B-NS3 competitive inhibitors with Ki values of 4.9 and 10.5 μM. The structure and activity relationship and the molecular docking revealed that L-proline, L-methionine and p-nitroaniline in 1 and 2 are the important characters in blocking the active site of NS2B-NS3 protease. Our current results suggest that the title dipeptidic scaffold represents a promising structural core to discover a new class of active NS2B-NS3 competitive inhibitors.
authors.affiliation: School of Pharmaceutical Sciences, and College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 211816, PR China. Electronic address: gczhou@njut.edu.cn.
authors.forename: Guo-Chun
authors.initials: GC
authors.lastname: Zhou
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Weng
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Shao
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Nie
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Decai
authors.initials: D
authors.lastname: Wang
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008715:Methionine / Q000737:chemistry; D062105:Molecular Docking Simulation; D011392:Proline / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D012703:Serotyping; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000085242:Viral Proteases
chemical_list: D000813:Anilides; D008715:Methionine; D011392:Proline; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: 4-(N,N′-dimethyl)-aminopyridine; 4-Nitroaniline; DCC; DCM; DENV; DMAP; Dengue virus NS2B-NS3 protease; EtOAc; EtOH; HQRJJHXKCFABSI-UONOGXRCSA-N; K(i); Methionine; Methionine–proline anilides; NS2B-NS3; Proline; SAR; TFA; dengue virus; dichloromethylene; dicyclohexylcarbodiimide; ethyl acetate; ethyl alcohol; inhibition constant; nonstructural protein 2B and 3; structure and activity relationship; trifluoroacetic acid