Structural insight into the binding interactions of NTPs and nucleotide analogues to RNA dependent RNA polymerase of SARS-CoV-2

Koulgi, Shruti; Jani, Vinod; N, Mallikarjunachari Uppuladinne V; Sonavane, Uddhavesh; Joshi, Rajendra

doi:10.1080/07391102.2021.1894985

Cited by 13 publications

(18 citation statements)

References 60 publications

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“…One of the earlier simulation studies reported by the authors had described the interacting residues of RdRP with nucleotide analogues [ 51 ]. Six nucleotide analogues were studied, namely, favipiravir, galidesivir, lamivudine, ribavirin, remdesivir and sofosbuvir.…”

Section: Resultsmentioning

confidence: 99%

“…The molecular docking was performed using DOCK 6 [ 50 ]. The protocol of flexible docking as reported in one of our earlier works on RdRP was followed [ 51 ]. The ligands were sorted based on the grid score, which is a measure of the effective binding of the ligand with the active site of the receptor molecule [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

“…Hence, for each of the four ligand-bound RdRP systems a cumulative of 100 ns simulation data was achieved. The simulation data for the ligand-free RdRP (RdRP-APO) system were obtained from the previously reported work by the authors of this article [ 51 ]. A cumulative of 250 ns simulation data for the RdRP-APO system was used for comparative study against the RdRP systems bound to phytochemicals.…”

Section: Methodsmentioning

confidence: 99%

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Natural plant products as potential inhibitors of RNA dependent RNA polymerase of Severe Acute Respiratory Syndrome Coronavirus-2

Koulgi

Jani

et al. 2021

PLoS ONE

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Drug repurposing studies targeting inhibition of RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have exhibited the potential effect of small molecules. In the present work a detailed interaction study between the phytochemicals from Indian medicinal plants and the RdRP of SARS-CoV-2 has been performed. The top four phytochemicals obtained through molecular docking were, swertiapuniside, cordifolide A, sitoindoside IX, and amarogentin belonging to Swertia chirayita, Tinospora cordifolia and Withania somnifera. These ligands bound to the RdRP were further studied using molecular dynamics simulations. The principal component analysis of these systems showed significant conformational changes in the finger and thumb subdomain of the RdRP. Hydrogen bonding, salt-bridge and water mediated interactions supported by MM-GBSA free energy of binding revealed strong binding of cordifolide A and sitoindoside IX to RdRP. The ligand-interacting residues belonged to either of the seven conserved motifs of the RdRP. These residues were polar and charged amino acids, namely, ARG 553, ARG 555, ASP 618, ASP 760, ASP 761, GLU 811, and SER 814. The glycosidic moieties of the phytochemicals were observed to form favourable interactions with these residues. Hence, these phytochemicals may hold the potential to act as RdRP inhibitors owing to their stability in binding to the druggable site.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Natural plant products as potential inhibitors of RNA dependent RNA polymerase of Severe Acute Respiratory Syndrome Coronavirus-2

Koulgi

Jani

et al. 2021

PLoS ONE

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“…These studies arrived at the same conclusion, i.e. that Lamivudine may bind with enough affinity to compete with CTP for the catalytic site of the SARS-CoV-2 RdRp, and putatively exert chain termination inhibition (81,82). In one of these studies, Koulgi et al 2).…”

Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19mentioning

confidence: 87%

“…In one of these studies, Koulgi et al. ( 82 ) carried out docking experiments similar to ours; however, they found higher binding energies for ATP (−45.67 kcal/mol), CTP (−43.97 kcal/mol), Remdesivir-TP (−48.22 kcal/mol), and Lamivudine-TP (−23.7 kcal/mol) than those we found for ATP (−13.10 kcal/mol), CTP (−13.58 kcal/mol), Remdesivir-TP (−16.88 kcal/mol) and Lamivudine-TP (−17.18 kcal/mol) ( Table 2 ). It may be difficult to explain the different binding energies observed between the study of Koulgi et al.…”

Section: Other Repurposing or Putative Reusage Of Annas And Lamivudine Against Sars-cov-2 And Covid-19mentioning

confidence: 99%

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

2021

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Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

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Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

Wang

Pan

et al. 2023

Drug Development Research

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Facing the sudden outbreak of coronavirus disease 2019 (COVID‐19), it is extremely urgent to develop effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Drug repurposing is a promising strategy for the treatment of COVID‐19. To identify the precise target protein of marketed medicines, we initiate a chemical biological program to identify precise target of potential antivirus drugs. In this study, two types of recombinant human coronavirus SARS‐CoV‐2 RdRp protein capturing probes with various photoaffinity labeling units were designed and synthesized based on the structure of FDA‐approved drugs stavudine, remdesivir, acyclovir, and aladenosine. Fortunately, it was found that one novel photoaffinity probe, RD‐1, could diaplayed good affinity with SARS‐CoV‐2 RdRp around the residue ARG_553. In addition, RD‐1 probe also exhibited potent inhibitory activity against 3CLpro protease. Taken together, our findings will elucidate the structural basis for the efficacy of marketed drugs, and explore a rapid and efficient strategy of drug repurposing based on the identification of new targets. Moreover, these results could also provide a scientific basis for the clinical application of marketed drugs.

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Structural insight into the binding interactions of NTPs and nucleotide analogues to RNA dependent RNA polymerase of SARS-CoV-2

Cited by 13 publications

References 60 publications

Natural plant products as potential inhibitors of RNA dependent RNA polymerase of Severe Acute Respiratory Syndrome Coronavirus-2

Natural plant products as potential inhibitors of RNA dependent RNA polymerase of Severe Acute Respiratory Syndrome Coronavirus-2

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients

Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

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