Identification of lead inhibitors of TMPRSS2 isoform 1 of SARS-CoV-2 target using neural network, random forest, and molecular docking

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for over 4 million confirmed cases of severe acute respiratory syndrome, of which more than 300,000 cases were confirmed to be dead as of May 2020. The virulent endocytotic activities of SARS-CoV-2 have been associated with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Previous studies on the viral activation of TMPRSS2 focused most often than not on the isoform 2 of TMPRSS2, but the isoform 1 (529 residues) has also been shown to be expressed in target cells and contribute to viral activation in host. The inhibition of TMPRSS2 has been reported to grossly reduce the pathogenic effects of SARS-CoV-2 endocytotic activities. In this study therefore, we developed two machine learning models using random forest classifier (RFC) and neural networks (NNs) based on 2251 serine protease inhibitors to screen a database of 21,000,000 virtual compounds. We screened the hit compounds using absorption, distribution, metabolism, and excretion (ADME) properties and finally docked the filtered compounds into the predicted binding site of TMPRSS2 isoform 1 homology model to determine their corresponding binding affinity and plausible molecular interactions. One (ASONN) and four (ASOIRFC1–4) lead compounds were obtained from the ADME-NN and RFC filtered hits, respectively, having better binding affinity and lead-likeness properties than those of camostat; this could be due to extensive hydrogen and hydrophobic interactions.