An interaction-based drug discovery screen explains known SARS-CoV-2 inhibitors and predicts new compound scaffolds

Abstract

The recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify Mpro inhibitors and potential novel compound scaffolds against SARS-CoV-2. The screen revealed a heterogeneous set of 692 potential Mpro inhibitors containing known ones such as Dasatinib, Amodiaquine, and Flavin mononucleotide, as well as so far untested chemical scaffolds. In a follow-up evaluation, we used publicly available data published almost two years after the screen to validate our results. In total, we are able to validate 17% of the top 100 predictions with publicly available data and can furthermore show that predicted compounds do cover scaffolds that are yet not associated with Mpro. Finally, we detected a potentially important binding pattern consisting of 3 hydrogen bonds with hydrogen donors of an oxyanion hole within the active side of Mpro. Overall, these results give hope that we will be better prepared for future pandemics and that drug development will become more efficient in the upcoming years.

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

“…Following the SARS-CoV-2 infection cycle, the viral major protease (MPro) is an essential component of SARS-CoV-2 replication and one of the principal targets for therapeutic research of this disease [48]. Large chemical databases have been screened using in silico studies that forecast the binding affinity and specificity of the compounds for MPro [49]. Through this method, a number of prospective drug candidates have been discovered, including the repurposing of previously used HIV protease inhibitors Lopinavir and Ritonavir [50,51].…”

3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

“…The 3CLpro has sparked significant interest in both the academic field and the pharmaceutical industry as a molecular target to inhibit viral replication and pathogenesis in various coronaviruses [ 19 ]. Several drug discovery strategies have been employed to find 3CLpro inhibitors, including drug repurposing, high-throughput virtual screening (HTVS), high-throughput screening (HTS), and structure- and ligand-based drug designs (SBDD and LBBD, respectively) [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Additionally, the strategy of exploring natural products as 3CLpro inhibitors has been one of the most important approaches for developing novel anti-SARS-CoV-2 agents [ 27 , 28 ].…”

A human primary airway microphysiological system infected with SARS-CoV-2 distinguishes the treatment efficacy between nirmatrelvir and repurposed compounds fluvoxamine and amodiaquine

“…This was a crucial finding since, following oral administration, amodiaquine is rapidly converted by hepatic cytochrome P450s into its most abundant metabolite, Nmonodesethylamodiaquine (Li et al, 2002). Interestingly, an in silico drug-protein complex interaction screen searching for potential inhibitors of Mpro, the main viral cysteine protease essential for cleavage of viral polyprotein, found amodiaquine to be among the potential inhibitors (Schake et al, 2023). However, these findings regarding a potential mechanism of antiviral action directly against the virion have not been biochemically verified.…”