Bepridil is potent against SARS-CoV-2 In Vitro

Vatansever, Erol C.; Yang, Kun; Kratch, Kaci C.; Drelich, Aleksandra; Cho, Chia-Chuan; Mellott, Drake M.; Xu, Shiqing; Tseng, Chien-Te K.; Liu, Wenshe Ray

doi:10.1101/2020.05.23.112235

Cited by 39 publications

(25 citation statements)

References 45 publications

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“…2, 3-Panel C). Intriguingly, this in-silico hypothesis has recently found two independent experimental validations, which have highlighted a mild inhibitory activity of Nelfinavir against the SARS-CoV-2 M pro (estimated between 250 and 600 μM) 25,26 . www.nature.com/scientificreports/ lar dynamics (MD) simulations were performed with an ACEMD3 engine on an Nvidia GPU cluster composed of 20 NVIDIA drivers, whose models go from GTX 1080 to Titan V 28 .…”

Section: Discussionmentioning

confidence: 87%

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Bolcato

Bissaro

Pavan

et al. 2020

Sci Rep

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Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019, which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited supervised molecular dynamics, an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole recognition pathway of Lopinavir, Ritonavir, and Nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease.

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Section: Discussionmentioning

confidence: 87%

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Bolcato

Bissaro

Pavan

et al. 2020

Sci Rep

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show abstract

“…As the individual enzymes offered different structural factors relevant for potent ligand-protein interaction, their consideration might improve the design of selective inhibitors. Regarding individual compounds, we identified four compounds which had the highest binding affinity toward more than a half of the analyzed proteases: nelfinavir ( 31 ) [ 4 , 37 , 38 ], lopinavir ( 32 ) [ 39 , 40 , 41 ], pimozide ( 33 ) [ 42 ], and baicalein ( 30 ) [ 43 ] ( Figure S24 ). Similarly, the aforementioned compounds, as well as both stereoisomers of beperidil ( 1-2 ) were predicted to interact with a large panel of known anti-targets.…”

Section: Results and Discussionmentioning

confidence: 99%

Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2

Fischer

Sellner

Mitusińska

et al. 2021

IJMS

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The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (Mpro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 Mpro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV Mpro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 Mpro inhibitors, as we report it, was not previously conducted.

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“… 45 This molecule has now been shown, after docking computations and experimental validations, to be potent against SARS-CoV-2 in vitro. 46 It is active on the virus main protease and most likely acts on endocytosis and, as such, could interfere with the entry of SARS-CoV-2 into mammalian host cells and slow down replication.…”

Section: Resultsmentioning

confidence: 99%

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

Villoutreix¹,

Krishnamoorthy²,

Tamouza³

et al. 2021

AABC

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Introduction There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Objective Based upon clinical observations, we proposed that some psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection. This observation is investigated in the light of experimental in vitro data on SARS-CoV-2. Methods SARS-CoV-2 high-throughput screening results are available at the NCATS COVID-19 portal. We investigated the in vitro anti-viral activity of many psychotropic and antihistaminic drugs using chemoinformatics approaches. Results and Discussion We analyze our clinical observations in the light of SARS-CoV-2 experimental screening results and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could protect people from SARS-CoV-2 infection; some of these molecules have very limited adverse effects and could be used as prophylactic drugs. Other cationic amphiphilic drugs used in other disease areas are also highlighted. Recent analyses of patient electronic health records reported by several research groups indicate that some of these molecules could be of interest at different stages of the disease progression. In addition, recently reported drug combination studies further suggest that it might be valuable to associate several cationic amphiphilic drugs. Taken together, these observations underline the need for clinical trials to fully evaluate the potentials of these molecules, some fitting in the so-called category of broad-spectrum antiviral agents. Repositioning orally available drugs that have moderate side effects and should act on molecular mechanisms less prone to drug resistance would indeed be of utmost importance to deal with COVID-19.

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Bepridil is potent against SARS-CoV-2 In Vitro

Cited by 39 publications

References 45 publications

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2

Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

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