Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling. Issue 10 (15th May 2019)

• Record Type: Journal Article
• Authors: Lee, Hyun; Ren, Jinhong; Pesavento, Russell P.; Ojeda, Isabel; Rice, Amy J.; Lv, Haining; Kwon, Youngjin; Johnson, Michael E.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 10(2019)
• Page Start: 1981
• Page End: 1989
• Publication Date: 2019-05-15
• Subjects: MERS-CoV Middle East Respiratory Syndrome Coronavirus -- SARS-CoV Severe Acute Respiratory Syndrome Coronavirus -- 3CLpro 3C-like protease -- PLpro papain-like protease -- HTS high-throughput screening -- SPR surface plasmon resonance -- MD molecular dynamic simulations; Middle East Respiratory Syndrome Coronavirus (MERS-CoV) -- Papain-like protease -- Small molecule inhibitor -- High-throughput screening -- Fragment screening -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.03.050
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The development of new therapeutic agents against the coronavirus causing Middle East Respiratory Syndrome (MERS) is a continuing imperative. The initial MERS-CoV epidemic was contained entirely through public health measures, but episodic cases continue, as there are currently no therapeutic agents effective in the treatment of MERS-CoV, although multiple strategies have been proposed. In this study, we screened 30, 000 compounds from three different compound libraries against one of the essential proteases, the papain-like protease (PL pro ), using a fluorescence-based enzymatic assay followed by surface plasmon resonance (SPR) direct binding analysis for hit confirmation. Mode of inhibition assays and competition SPR studies revealed two compounds to be competitive inhibitors. To improve upon the inhibitory activity of the best hit compounds, a small fragment library consisting of 352 fragments was screened in the presence of each hit compound, resulting in one fragment that enhanced the IC50 value of the best hit compound by 3-fold. Molecular docking and MM/PBSA binding energy calculations were used to predict potential binding sites, providing insight for design and synthesis of next-generation compounds.