Although several vaccines and therapeutic antibodies have been developed against SARS-CoV-2, the major drawback of these therapies is the presence of frequent mutations on the S protein. Such mutations can render antibodies and vaccines ineffective, creating a need for drugs that target other SARS-CoV-2 proteins. The papain-like protease (PLpro) of SARS-CoV-2 plays an important role in viral replication and has also been associated with dysregulation of host inflammation and the antiviral immune response, making it an attractive target for drug development. To address this issue, we have developed a drug discovery workflow that applies both in silico and in vitro methods to discover potential lead molecules. The first step was to develop a custom protease inhibitor library assembled from both commercially available targeted libraries and the ChEMBL database as well as prefilter the comopunds using in-house developed medicinal chemistry filtering pipeline. Ensemble molecular docking was performed for the open and closed conformations of PLpro (CmDock software). For the top 30 best scoring hit compounds, the binding free energy was calculated over 100 ns molecular dynamics simulations (MD) using the Linear interaction energy (LIE) method as implemented in Q software. The <i>in-vitro</i> inhibitory activities of the hits against PLpro were determined using fluorimetric measurements to discover new structurally related micromolar inhibitors with xanthine and 1,4,6-Triaza-7-indenone scaffolds. The small-molecule compounds represent new non-covalent and synthetically tractable inhibitors suitable for further optimization. Moreover, additional free energy calculations were performed using the thermodynamic integration method (CHARMM software) to gain detailed insight into the binding modes of the identified PLpro inhibitors.

Identification of new xanthine and 1,4,6-Triaza-7-indenone scaffold SARS-CoV-2 PLpro inhibitors

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ACS Fall 2022

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