02932nas a2200313 4500008004100000022001400041245013200055210006900187260000800256520189100264653001602155653001302171653001102184653000902195653003302204653002302237653000902260653002102269100002202290700002502312700002302337700001902360700002602379700002702405700001702432700002002449700002502469856012402494 2020 eng d a0739-110200aDiscovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease0 aDiscovery of potential multitargetdirected ligands by targeting  cMAY3 a

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M-Pro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M-Pro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae M-Pro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of M-Pro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M-Pro. In agreement with this, we performed screening of similar to 7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M-Pro as the primary target. We identified several natural molecules like delta-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 M-Pro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection. Communicated by Ramaswamy H. Sarma

10aCoronavirus10aCOVID-1910ahACE-210aMPro10amulti-target-directed ligand10aprotease inhibitor10aRdRp10aSARS-CoV-2 virus1 aJoshi, Rakesh, S.1 aJagdale, Shounak, S.1 aBansode, Sneha, B.1 aShankar, Shiva1 aTellis, Meenakshi, B.1 aPandya, Vaibhav, Kumar1 aChugh, Anita1 aGiri, Ashok, P.1 aKulkarni, Mahesh, J. uhttps://library.ncl.res.in/content/discovery-potential-multi-target-directed-ligands-targeting-host-specific-sars-cov-202341nas a2200289 4500008004100000022001400041245008700055210006900142260000900211300001400220490000800234520143200242653002101674653001101695653001801706653003301724653001501757100002201772700002001794700002501814700001801839700001801857700002101875700002301896700001701919856011501936 2021 eng d a0011-389100aAntiviral drugs prioritization for COVID-19 management based on rational selection0 aAntiviral drugs prioritization for COVID19 management based on r cMAY  a1464-14700 v1203 a

The SARS-CoV-2 infection has resulted in COVID-19 pandemic worldwide. It has infected around 0.1 billion individuals and caused 2 million fatalities across the globe till mid-January 2021. Drug repurposing has been utilized as the most preferred therapeutic intervention for COVID-19 mitigation due to its necessity and feasibility. To prioritize therapeutic regime against COVID-19, we used 61 antiviral drugs and their combinations. Selected molecules were subjected to virtual screening against: (i) human angiotensin-converting enzyme 2 receptor binding domain (hACE-2) which serves as an anchor for virus attachment and entry, (ii) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication, and (iii) SARS-CoV-2 main protease (M-Pro) needed for viral polyprotein slab proteolytic processing. Based on docking score, pharmacodynamic and pharmacokinetic parameters, combinations of Daclatasvir, Elbasvir, Indinavir, Ledipasvir, Paritaprevir and Rilpivirine were analysed further. Our analysis suggested Sofosbuvir in combination with Ledipasvir and Daclatasvir as potential therapeutic agents for SARS-CoV-2. The combined score suggests that these combinations have superior anti-SARS-CoV-2 potential than Remdesivir and other investigational drugs. The present work provides a rationale-based approach to select drugs with possible anti-SARS-CoV-2 activity for further clinical evaluation.

10aDrug repurposing10ahACE-210amain protease10aRNA dependent RNA polymerase10aSARS-CoV-21 aJoshi, Rakesh, S.1 aGiri, Ashok, P.1 aKulkarni, Mahesh, J.1 aGupta, Mahesh1 aVerma, Savita1 aChaudhry, Dhruva1 aDeshmukh, Narendra1 aChugh, Anita uhttps://library.ncl.res.in/content/antiviral-drugs-prioritization-covid-19-management-based-rational-selection02575nas a2200325 4500008004100000245017700041210006900218260000800287300000800295490000700303520150700310653001401817653001301831653001601844653001501860653001501875653001501890100001901905700002401924700002201948700001701970700002301987700001802010700001802028700001602046700002102062700001802083700002202101856012602123 2023 eng d00aComprehensive molecular and clinical investigation of approved Anti-HCV drugs repurposing against SARS-CoV-2 infection: a glaring gap between benchside and bedside medicine0 aComprehensive molecular and clinical investigation of approved A cMAR a5150 v113 a

The limited availability of effective treatment against SARS-CoV-2 infection is a major challenge in managing COVID-19. This scenario has augmented the need for repurposing anti-virals for COVID-19 mitigation. In this report, the anti-SARS-CoV-2 potential of anti-HCV drugs such as daclatasvir (DCV) or ledipasvir (LDP) in combination with sofosbuvir (SOF) was evaluated. The binding mode and higher affinity of these molecules with RNA-dependent-RNA-polymerase of SARS-CoV-2 were apparent by computational analysis. In vitro anti-SARS-CoV-2 activity depicted that SOF/DCV and SOF/LDP combination has IC50 of 1.8 and 2.0 mu M, respectively, comparable to remdesivir, an approved drug for COVID-19. Furthermore, the clinical trial was conducted in 183 mild COVID-19 patients for 14 days to check the efficacy and safety of SOF/DCV and SOF/LDP compared to standard of care (SOC) in a parallel-group, hybrid, individually randomized, controlled clinical study. The primary outcomes of the study suggested no significant difference in negativity after 3, 7 and 14 days in both treatments. None of the patients displayed any worsening in the disease severity, and no mortality was observed in the study. Although, the post hoc exploratory analysis indicated significant normalization of the pulse rate showed in SOF/DCV and SOF/LDP treatment vs. SOC. The current study highlights the limitations of bench side models in predicting the clinical efficacy of drugs that are planned for repurposing.

10aantiviral10aCOVID-1910adaclatasvir10aledipasvir10aSARS-CoV-210asofosbuvir1 aBansode, Sneha1 aSingh, Pawan, Kumar1 aTellis, Meenakshi1 aChugh, Anita1 aDeshmukh, Narendra1 aGupta, Mahesh1 aVerma, Savita1 aGiri, Ashok1 aKulkarni, Mahesh1 aJoshi, Rakesh1 aChaudhary, Dhruva uhttps://library.ncl.res.in/content/comprehensive-molecular-and-clinical-investigation-approved-anti-hcv-drugs-repurposing