Over the past three years, significant progress has been made in the development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting in the emergence of new viral strains that can be resistant to the drugs used currently in the clinic necessitate the development of novel potent and broad therapeutic agents targeting different vulnerable spots of the viral proteins. In this study, two deep learning generative models were developed and used in combination with molecular modeling tools for de novo design of small molecule compounds that can inhibit the catalytic activity of SARS-CoV-2 main protease (Mpro), an enzyme critically important for mediating viral replication and transcription. As a result, the seven best scoring compounds that exhibited low values of binding free energy comparable with those calculated for two potent inhibitors of Mpro, via the same computational protocol, were selected as the most probable inhibitors of the enzyme catalytic site. In light of the data obtained, the identified compounds are assumed to present promising scaffolds for the development of new potent and broad-spectrum drugs inhibiting SARS-CoV-2 Mpro, an attractive therapeutic target for anti-COVID-19 agents.

De novo design of 95 775 potential ligands of SARS-CoV-2 main protease (Mpro), playing an important role in the process of virus replication, was carried out using a deep learning generative neural network that was developed previously based on artificial intelligence technologies. Molecular docking and molecular dynamics methods were used to evaluate the binding affinity of these molecules to the catalytic site of the enzyme. As a result, 7 leading compounds exhibiting Gibbs free energy low values comparable with the values obtained using an identical computational protocol for two potent non-covalent SARS-CoV-2 Mpro inhibitors used in calculations as a positive control were selected. The results obtained indicate the promise of applying identified compounds for development of new antiviral drugs able to inhibit the catalytic activity of SARSCoV-2 Mpro.

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