Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline

Abstract

A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 in Wuhan, China and reached most corners of the globe in less than two months. In just over a year since the initial infections, COVID-19 infected almost 100 million people worldwide. Although similar to SARS-CoV and MERS-CoV, SARS-CoV-2 has resisted treatments that are effective against other coronaviruses. Crystal structures of two SARS-CoV-2 proteins, spike protein and main protease, have been reported and can serve as targets for studies in neutralizing this threat. We have employed molecular docking, molecular dynamics simulations, and machine learning to identify from a library of 26 million molecules possible candidate compounds that may attenuate or neutralize the effects of this virus. The viability of selected candidate compounds against SARS-CoV-2 was determined experimentally by biolayer interferometry and FRET-based activity protein assays along with virus-based assays. In the pseudovirus assay, imatinib and lapatinib had IC50 values below 10 μM, while candesartan cilexetil had an IC50 value of approximately 67 µM against Mpro in a FRET-based activity assay. Comparatively, candesartan cilexetil had the highest selectivity index of all compounds tested as its half-maximal cytotoxicity concentration 50 (CC50) value was the only one greater than the limit of the assay (>100 μM).

Defective ORF8 dimerization in SARS-CoV-2 delta variant leads to a better adaptive immune response due to abrogation of ORF8-MHC1 interaction

“…ORF8 is also involved in suppression antiviral proteins from INFγ [14]. SARS-CoV-2 drug or vaccines were using spike protein as an important target [20,37,38,41], but ORF8 can be also targeted for producing therapeutic approaches. These studies shows that ORF8 is involved in modulating the host immune response and majorly by downregulating MHC-I.…”

Drug repurposing for identification of potential spike inhibitors for SARS-CoV-2 using molecular docking and molecular dynamics simulations

“…Saquinavir was also indicated as a viable inhibitor of M pro after applying QSAR and HQSAR models [57] , while the latter compound was identified as an M pro inhibitor using molecular docking [58] . Candesartan cilexetil, which according to our study can inhibit spike from various lineages, had an IC50 value of approximately 67 μM against M pro in a FRET-based activity assay [59] . This drug can have a dual effect as it is used in high blood pressure treatment, which is also one of the hallmarks of COVID-19 due to the SARS-CoV-2 influence on the RSS.…”

Pose Classification Using Three-Dimensional Atomic Structure-Based Neural Networks Applied to Ion Channel–Ligand Docking

“…In particular, recent studies have shown that vHTS-based methods are capable of identifying small-molecule inhibitors against SARS-CoV-2. 1 − 3 …”

“…3D-CNN-based approaches have been extensively used to predict the binding affinity of complexes. 1 , 14 Unlike the previous approaches, we propose to employ it as a pose classifier to filter out false positive docking poses to improve the accuracy of virtual screening. Moreover, as an alternative to the 3D-CNN-based method, we present another neural network approach (PCN) that directly captures global information on 3D atom structures without voxelizing them into a 3D voxel grid.…”