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Computational Protein Design for COVID-19 Research and Emerging Therapeutics.

ABSTRACT: As the world struggles with the ongoing COVID-19 pandemic, unprecedented obstacles have continuously been traversed as new SARS-CoV-2 variants continually emerge. Infectious disease outbreaks are unavoidable, but the knowledge gained from the successes and failures will help create a robust health management system to deal with such pandemics. Previously, scientists required years to develop diagnostics, therapeutics, or vaccines; however, we have seen that, with the rapid deployment of high-throughput technologies and unprecedented scientific collaboration worldwide, breakthrough discoveries can be accelerated and insights broadened. Computational protein design (CPD) is a game-changing new technology that has provided alternative therapeutic strategies for pandemic management. In addition to the development of peptide-based inhibitors, miniprotein binders, decoys, biosensors, nanobodies, and monoclonal antibodies, CPD has also been used to redesign native SARS-CoV-2 proteins and human ACE2 receptors. We discuss how novel CPD strategies have been exploited to develop rationally designed and robust COVID-19 treatment strategies.

SUBMITTER: Kalita P

PROVIDER: S-EPMC10042144 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Computational Protein Design for COVID-19 Research and Emerging Therapeutics.

Kalita Parismita P Tripathi Timir T Padhi Aditya K AK

ACS central science 20230320 4

As the world struggles with the ongoing COVID-19 pandemic, unprecedented obstacles have continuously been traversed as new SARS-CoV-2 variants continually emerge. Infectious disease outbreaks are unavoidable, but the knowledge gained from the successes and failures will help create a robust health management system to deal with such pandemics. Previously, scientists required years to develop diagnostics, therapeutics, or vaccines; however, we have seen that, with the rapid deployment of high-thr ...[more]

PMID: 37122454

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Project description:BackgroundIn 2003, the first case of severe acute respiratory syndrome coronavirus (SARS-CoV) was recorded. Coronaviruses (CoVs) have caused a major outbreak of human fatal pneumonia. Currently, there is no specific drug or treatment for diseases caused by SARS CoV 2. Computational approach that adopts dynamic models is widely accepted as indispensable tool in drug design but yet to be exploited in covid-19 in Zaria, Nigeria. In this study, steps were taken to advance on the successful achievements in the field of covid-19 drug, with the aid of in silico drug design technique, to create novel inhibitor drug candidates with better activity. In this study, one thousand human immunodeficiency virus (HIV1) antiviral chemical compounds from www.bindingBD.org were docked on the SARS CoV 2 main protease protein data bank identification number 6XBH (PDB ID: 6XBH) and the molecular docking score were ranked in order to identify the compounds with the highest inhibitory effects, and easy selection for future studies.ResultsThe docking studies showed some interesting results. Inhibitors with Index numbers 331, 741, and 819 had the highest binding affinity. Similarly, inhibitors with Index number 441, 847, and 46 had the lowest hydrogen bond energy. Inhibitor with index number 331 was reported with the lowest value (- 48.38kCal/mol). Five new compounds were designed from the selected six (6) compounds with the best binding score giving a total of thirty (30) novel compounds. The low binding energy of inhibitor with index no. 847b is unique, as most of the interaction energies are of H-bond type with amino acids (Thr26, Gly143, Ser144, Cys145, Glu166, Gln189, Hie164, Met49, Thr26, Thr25, Thr190, Asn142, Met165) resulting in an overall negative value (-16.31 kCal/mol) making it the best of all the newly designed inhibitors.ConclusionsThe novel inhibitor is 2-(2-(5-amino-2-((((3-aminobenzyl)oxy)carbonyl)amino)-5-oxopentanamido)-4-(2-(tert-butyl)-4-oxo-4-(pentan-3-ylamino) butanamido)-3-hydroxybutyl) benzoic acid. The improvement it has over the parent inhibitor is from the primary amine group attached to meta position of first benzene ring and the carboxyl group attached to the ortho position of the second benzene ring. The molecular dynamics studies also show that the novel inhibitor remains stable after the study. This result makes it a better drug candidate against SARS CoV 2 main protease when compared with the co-crystallized inhibitor or any of the 1000 docked inhibitors.Supplementary informationThe online version contains supplementary material available at 10.1186/s42269-022-00892-z.

Dataset Information

Computational Protein Design for COVID-19 Research and Emerging Therapeutics.

Publications

Computational Protein Design for COVID-19 Research and Emerging Therapeutics.

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