Emerging strategies on in silico drug development against COVID-19: challenges and opportunities

Yadav, Madhu; Dhagat, Swasti; Eswari, J. Satya

doi:10.1016/j.ejps.2020.105522

Cited by 30 publications

(24 citation statements)

References 177 publications

(251 reference statements)

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“…The viral proteases 3CL pro and PL pro are the key proteins for the proteolytic processing of the polyproteins that are helpful for initiating replication, whereas RdRp is a vital replication machinery of the virus, making multiple copies of the RNA genome. Therefore, these proteins have been considered as promising drug targets in the treatment of viral diseases (Fehr and Perlman, 2015;Yadav et al, 2020). Recently, several drugs including Lopinavir, Ritonavir, Remdesivir, and Favipiravir were repurposed and are currently under clinical trials to assess their anti-viral efficacy and safety for the treatment of COVID-19 (Drożdżal et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

et al. 2021

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The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, a very small number of remedies have been to be found effective against SARS-CoV-2 infection. Therefore, further research is required to achieve a lasting solution against this deadly disease. Repurposing available drugs and evaluating natural product inhibitors against target proteins of SARS-CoV-2 could be an effective approach to accelerate drug discovery and development. With this strategy in mind, we derived Marine Natural Products (MNP)-based drug-like small molecules and evaluated them against three major target proteins of the SARS-CoV-2 virus replication cycle. A drug-like database from MNP library was generated using Lipinski’s rule of five and ADMET descriptors. A total of 2,033 compounds were obtained and were subsequently subjected to molecular docking with 3CLpro, PLpro, and RdRp. The docking analyses revealed that a total of 14 compounds displayed better docking scores than the reference compounds and have significant molecular interactions with the active site residues of SARS-CoV-2 virus targeted proteins. Furthermore, the stability of docking-derived complexes was analyzed using molecular dynamics simulations and binding free energy calculations. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, binding affinity, and molecular interactions. Our investigation identified two hit compounds against each targeted proteins displaying stable behavior, higher binding affinity and key residual molecular interactions, with good in silico pharmacokinetic properties, therefore can be considered for further in vitro studies.

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Section: Discussionmentioning

confidence: 99%

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

et al. 2021

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“…At present, there is no definite antiviral drug to accelerate the probability of negativeconversion for SARS-CoV-2 (Parvathaneni and Gupta, 2020; Yadav et al, 2020), the development of a vaccine (Torreele, 2020; Wang et al, 2020) appears to be the last straw for prevention and control of COVID-19. The development of new antiviral requires a considerable length of time and effort for drug design and validation.…”

Section: Disscusionmentioning

confidence: 99%

Chinese medicine (Q-14) in the Treatment of Patients with Coronavirus Disease 2019 (COVID-19): A Single-center, Open label, Randomised Controlled Trial

Liu

Yang

Liu

et al. 2021

Preprint

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OBJECTIVETo evaluate the efficacy and safety of Chinese medicine (Q-14) plus standard care compared with standard care alone in adult with coronavirus disease 2019 (COVID-19).Study DESIGNSingle-center, open label, randomised controlled trial.SETTINGWuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020.PARTICIPANTS204 patients with laboratory confirmed COVID-19 were randomised in to treatment group and control group, which was 102 patients each group.INTERVENTIONSIn treatment group, Q-14 was administrated at 10g (granules), twice daily for 14 days and plus standard care. In control group, patients were given standard care alone for 14 days.MAIN OUTCOME MEASUREThe primary outcome was conversion time of SARS-CoV-2 viral assay. Adverse events were analyzed in the safety population.RESULTSAmong 204 patients, 195 were analyzed according to the intention to treat principle. There were 149 patients (71 vs. 78 in treatment group and control group respectively) turning to negative via SARS-CoV-2 viral assay. No statistically significance showed in conversion time between treatment group and control group (FAS: Median (IQR): 10.00 (9.00-11.00) vs. 10.00 (9.00-11.00); Mean rank: 67.92 vs. 81.44; P=0.051.). Time to recovery of fever was shorter in treatment group as compared in control group. The disappearance rate of symptom in cough, fatigue, chest discomfort was significantly higher in treatment group. In chest computed tomography (Chest CT) examinations, overall evaluation of chest CT examination after treatment compared with baseline showed more patients improved in treatment group .There were no significant differences in the other outcomes.CONCLUSIONAdministration of Q-14 on standard care for COVID-19 was useful for improvement of symptoms (such as fever, cough, fatigue and chest discomfort), while did not result in a significantly higher probability of negative conversion of SARS-CoV-2 viral assay. No serious adverse events were reported.TRIAL REGISTRATIONChiCTR2000030288

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“…The use of computational methods has been suggested as a viable alternative for the faster and cheaper discovery of COVID-19 therapeutic molecules [ 28 , 29 , 30 , 31 , 32 , 33 ]. Natural products are used as COVID-19 remedies [ 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

et al. 2021

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Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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Emerging strategies on in silico drug development against COVID-19: challenges and opportunities

Cited by 30 publications

References 177 publications

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

Chinese medicine (Q-14) in the Treatment of Patients with Coronavirus Disease 2019 (COVID-19): A Single-center, Open label, Randomised Controlled Trial

Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

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