Drug repurposing is an important approach to the assignment of already approved drugs for new indications. This technique bypasses some steps in the traditional drug approval system, which saves time and lives in the case of pandemics. Direct acting antivirals (DAAs) have repeatedly repurposed from treating one virus to another. In this study, 16 FDA-approved hepatitis C virus (HCV) DAA drugs were studied to explore their activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human and viral targets. Among the 16 HCV DAA drugs, telaprevir has shown the best in silico evidence to work on both indirect human targets (cathepsin L [CTSL] and human angiotensin-converting enzyme 2 [hACE2] receptor) and direct viral targets (main protease [M^pro]). Moreover, the docked poses of telaprevir inside both hACE2 and M^pro were subjected to additional molecular dynamics simulations monitored by calculating the binding free energy using MM-GBSA. In vitro analysis of telaprevir showed inhibition of SARS-CoV-2 replication in cell culture (IC₅₀ = 11.552 μM, CC₅₀ = 60.865 μM, and selectivity index = 5.27). Accordingly, based on the in silico studies and supported by the presented in vitro analysis, we suggest that telaprevir may be considered for therapeutic development against SARS-CoV-2.

Pharmacovigilance is the pharmacological science that focuses on the safe and appropriate use of drugs.Variability in response to drug therapy in both terms of safety and efficacy is highly related to patient's personal genomics. Hence, pharmacovigilance considers pharmacogenomics methodologies in the evaluation of medicinal products. The aim of this work is to introduce the pharmacovigilance/ pharmacogenomics insilico pipeline (PHARMIP) that uses the drug (or drug candidate) digital structure and the advances in bioinformatics tools and databases to figure-out the genetic factors underlying the drug reported adverse reactions (ADRs).PHARMIP uses user-friendly freely available bioinformatics resources to help pharmacovigilance and pharmacogenomics scientists with minimal bioinformatics experience to retrieve helpful information for their daily basis activities. Also, PHARMIP could help the advances in precision medicine in a drug-centric approach as it can be used to reveal genetic risk factors for certain drug ADRs. Domperidone was used as an example to the application of PHARMIP as the pipeline was initially developed during the insilico exploration of domperidone cardiotoxic ADRs. Method is composed of 3 main steps: •Preparing the drug off-label targets (OLT) list.•Retrieving the related diseases/ adverse reactions (DA) list.•Analysis of DA list to get answers.

Introduction Direct-acting antivirals (DAAs) represent a breakthrough in hepatitis C virus (HCV) treatment as they directly inhibit HCV nonstructural (NS) proteins (NS3/4A, NS5A, and NS5B). However, ongoing debates exist regarding their relationship with hepatocellular carcinoma (HCC) whose incidence is widely debated among investigators. This study was conducted to identify host pharmacogenetic factors that may influence HCC incidence upon using HCV DAAs. Materials and methods Details regarding 16 HCV DAAs were collected from literature and DrugBank database. Digital structures of these drugs were fed into the pharmacogenomics/pharmacovigilance in-silico pipeline (PHARMIP) to predict the genetic factors that may underpin HCC development. Results We identified 184 unique genes and 40 unique variants that may have key answers for the DAA/HCC paradox. These findings could be used in different methods to aid in the precise application of HCV DAAs and minimize the proposed risk for HCC. All results could be accessed at: https://doi.org/10.17632/8ws8258hn3.2. Discussion All the identified factors are evidence related to HCC and significantly predicted by PHARMIP as DAA targets. We discuss some examples of the methods of using these results to address the DAA/HCC controversy based on the following three primary levels: 1 - individual DAA drug, 2 - DAA subclass, and 3 - the entire DAA class. Further wet laboratory investigation is required to evaluate these results.