Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model

Abstract

Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19.

In silico identification of available drugs targeting cell surface BiP to disrupt SARS-CoV-2 binding and replication: Drug repurposing approach

“…Similar to velpatasvir, paritaprevir is an antiviral agent against the HCV protease complex that gained a considerable amount of attention in the studies of COVID-19. Through tools like artificial intelligence (AI) deep learning, molecular docking, and, in some studies, molecular dynamics simulation, these investigations unanimously suggested the potential of paritaprevir in inhibiting viral RdRp, S protein, and proteases ( Manikyam and Joshi, 2020 , Shah et al, 2020 , Alamri et al, 2020 , Khan et al, 2020 , Choi et al, 2020 ). Our results expand the current paradigm and suggest that paritaprevir may also be used to target the NBD of csBiP, thereby sabotaging viral activities.…”

Computational and in vitro experimental analyses of the Anti-COVID-19 potential of Mortaparib and MortaparibPlus

“…proteins are some of the major targets of the coronaviruses, their excessive suppression by targeted therapies may result into the appearance of unprecedented collateral adverse effects such as the male infertility, frequent respiratory infections, and hypertension (47,48).…”

Computational and in vitro experimental analyses of the anti-COVID-19 potential of Mortaparib and MortaparibPlus

“…ACE2, on the other hand, is commonly known to physiologically catalyze the hydrolysis of angiotensin II to angiotensin and contribute to vasodilatation [ 28 , 29 ], and to pathologically facilitate SARS-CoV-2 and similar infections [ 46 ]. Thus, while the TMPRSS2 and ACE2 proteins are some of the major targets of the coronaviruses, their excessive suppression by targeted therapies may result into the appearance of unprecedented collateral adverse effects such as the male infertility, frequent respiratory infections, and hypertension [ 47 , 48 ]. Another crucial target to fight against SARS-CoV-2 is M pro , which cleaves the polyprotein into functional proteins to help in its replication process [ 49 ].…”