Computational anti-COVID-19 drug design: progress and challenges.
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ABSTRACT:
SUBMITTER: Wang J
PROVIDER: S-EPMC8690229 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The expeditious and world pandemic viral disease of new coronavirus (SARS-CoV-2) has formed a prompt urgency to discover auspicious target-based ligand for the treatment of COVID-19. Symptoms of novel coronavirus disease (COVID-19) typically include dry cough, fever, and shortness of breath. Recent studies on many COVID-19 patients in Italy and the United Kingdom found increasing anosmia and ageusia among the COVID-19-infected patients. SARS-CoV-2 possibly infects neurons in the nasal passage and disrupts the senses of smell and taste, like other coronaviruses, such as SARS-CoV and MERS-CoV that could target the central nervous system. Developing a drug based on the T2Rs might be of better understanding and worth finding better molecules to act against COVID-19. In this research, we have taken a taste receptor agonist molecule to find a better core molecule that may act as the best resource to design a drug or corresponding derivatives. Based on the computational docking studies, the antibiotic tobramycin showed the best interaction against 6LU7 COVID-19 main protease. Aromatic carbonyl functional groups of the molecule established intermolecular hydrogen bonding interaction with GLN189 amino acid and it showed the two strongest carbonyl interactions with receptor protein resulting in a glide score of -11.159. To conclude, depending on the molecular recognition of the GPCR proteins, the agonist molecule can be recognized to represent the cell secondary mechanism; thus, it provides enough confidence to design a suitable molecule based on the tobramycin drug.
| S-EPMC8416165 | biostudies-literature
Project description:Background In 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. Results The 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. Conclusions The 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 Information The online version contains supplementary material available at 10.1186/s42269-022-00892-z.
| S-EPMC9284480 | biostudies-literature
Project description:Enzymes are powerful biocatalysts, however, so far there is still a large gap between the number of enzyme-based practical applications and that of naturally occurring enzymes. Multiple experimental approaches have been applied to generate nearly all possible mutations of target enzymes, allowing the identification of desirable variants with improved properties to meet the practical needs. Meanwhile, an increasing number of computational methods have been developed to assist in the modification of enzymes during the past few decades. With the development of bioinformatic algorithms, computational approaches are now able to provide more precise guidance for enzyme engineering and make it more efficient and less laborious. In this review, we summarize the recent advances of method development with significant biological outcomes to provide important insights into successful computational protein designs. We also discuss the limitations and challenges of existing methods and the future directions that should improve them.
| S-EPMC3962085 | biostudies-literature
Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still a worldwide concern, with little to no sign of a decreasing trend. There is a general consensus that normal life will be hampered until a safe and effective vaccine strategy is available and globally administered. Numerous countries have accelerated the clinical trials process for the development of a successful COVID-19 treatment, with over 200 candidates presently available for testing against SARS-CoV-2. Here, we provide an overview of the COVID-19 vaccine candidates currently in development, discuss the scientific and practical challenges associated with COVID-19 vaccine design, and share the potential strategies that could be exploited for vaccine design success.
| S-EPMC7835609 | biostudies-literature
Project description:Seasonal and pandemic influenza have caused high morbidity and mortality worldwide. Recent emergence of influenza A H5N1 and H1N1 strains has heightened concern, especially as a result of their drug resistance. The life cycle of influenza viruses has been well studied and nearly all the viral proteins are becoming potential therapeutic targets. In this review, we present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance.
| S-EPMC3459301 | biostudies-literature
Project description:Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment.
| S-EPMC4876017 | biostudies-literature
Project description:Coronaviruses are a large group of viruses known to cause illnesses that vary between the common cold and more severe diseases to include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). A novel coronavirus was identified in December 2019 in Wuhan city, Hubei province, China. This virus represents a new strain that has not been previously identified in humans. The virus is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease is called coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) declared the novel coronavirus outbreak a global pandemic in March 2020. Despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with more than 1,948,617 laboratory-confirmed cases and over 121,846 deaths worldwide. Currently, no specific medication is recommended to treat COVID-19 patients. However, governments and pharmaceutical companies are struggling to quickly find an effective drug to defeat the coronavirus. In the current review, we summarize the existing state of knowledge about COVID-19, available medications, and treatment options. Favilavir is an antiviral drug that is approved in Japan for common influenza treatment and is now approved to treat symptoms of COVID-19 in China. Moreover, Chloroquine and hydroxychloroquine, drugs used to treat malaria and arthritis, respectively, were recommended by the National Health Commission of the People's Republic of China for treatment of COVID-19. Presently, chloroquine and hydroxychloroquine are under investigation by the US Food and Drug Administration (FDA) as a treatment for COVID-19. The first COVID-19 vaccine is not expected to be ready for clinical trials before the end of the year.
| S-EPMC7166307 | biostudies-literature
Project description:The number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients keeps rising in most of the European countries despite the pandemic precaution measures. The current antiviral and anti-inflammatory therapeutic approaches are only supportive, have limited efficacy, and the prevention in reducing the transmission of SARS-CoV-2 virus is the best hope for public health. It is presumed that an effective vaccination against SARS-CoV-2 infection could mobilize the innate and adaptive immune responses and provide a protection against severe forms of coronavirus disease 2019 (COVID-19) disease. As the race for the effective and safe vaccine has begun, different strategies were introduced. To date, viral vector-based vaccines, genetic vaccines, attenuated vaccines, and protein-based vaccines are the major vaccine types tested in the clinical trials. Over 80 clinical trials have been initiated; however, only 18 vaccines have reached the clinical phase II/III or III, and 4 vaccine candidates are under consideration or have been approved for the use so far. In addition, the protective effect of the off-target vaccines, such as Bacillus Calmette-Guérin and measles vaccine, is being explored in randomized prospective clinical trials with SARS-CoV-2-infected patients. In this review, we discuss the most promising anti-COVID-19 vaccine clinical trials and different vaccination strategies in order to provide more clarity into the ongoing clinical trials.
| S-EPMC7900461 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 1.4 million deaths worldwide. Repurposing existing drugs offers the fastest opportunity to identify new indications for existing drugs as a stable solution against coronavirus disease 2019 (COVID-19). The SARS-CoV-2 main protease (Mpro) is a critical target for designing potent antiviral agents against COVID-19. In this study, we identify potential inhibitors against COVID-19, using an amalgam of virtual screening, molecular dynamics (MD) simulations, and binding-free energy approaches from the Korea Chemical Bank drug repurposing (KCB-DR) database. The database screening of KCB-DR resulted in 149 binders. The dynamics of protein-drug complex formation for the seven top scoring drugs were investigated through MD simulations. Six drugs showed stable binding with active site of SARS-CoV-2 Mpro indicated by steady RMSD of protein backbone atoms and potential energy profiles. Furthermore, binding free energy calculations suggested the community-acquired bacterial pneumonia drug ceftaroline fosamil and the hepatitis C virus (HCV) protease inhibitor telaprevir are potent inhibitors against Mpro. Molecular dynamics and interaction analysis revealed that ceftaroline fosamil and telaprevir form hydrogen bonds with important active site residues such as Thr24, Thr25, His41, Thr45, Gly143, Ser144, Cys145, and Glu166 that is supported by crystallographic information of known inhibitors. Telaprevir has potential side effects, but its derivatives have good pharmacokinetic properties and are suggested to bind Mpro. We suggest the telaprevir derivatives and ceftaroline fosamil bind tightly with SARS-CoV-2 Mpro and should be validated through preclinical testing.
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Project description:The emergence of a novel coronavirus viz., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 and its subsequent substantial spread produced the coronavirus disease 2019 (COVID-19) pandemic worldwide. Given its unprecedented infectivity and pathogenicity, the COVID-19 pandemic had a devastating impact on human health, and its clinical management has been a great challenge, which has led to the development and speedy trials of several vaccine candidates against SARS-CoV-2 at an exceptional pace. As a result, several COVID-19 vaccines were made commercially available in the first half of 2021. Although several COVID-19 vaccines showed promising results, crucial insights into their epidemiology, protective mechanisms, and the propensities of reinfection are not largely reviewed. In the present report, we provided insights into the prospects of vaccination against COVID-19 and assessed diverse vaccination strategies including DNA, mRNA, protein subunits, vector-based, live attenuated, and inactivated whole/viral particle-based vaccines. Next, we reviewed major aspects of various available vaccines approved by the World Health Organization and by the local administrations to use against COVID-19. Moreover, we comprehensively assessed the success of these approved vaccines and also their untoward effects, including the possibility of reinfection. We also provided an update on the vaccines that are under development and could be promising candidates in the future. Conclusively, we provided insights into the COVID-19 vaccine epidemiology, their potency, and propensity for SARS-CoV-2 reinfection, while a careful review of their current status, strategies, success, and future challenges was also presented.
| S-EPMC8615473 | biostudies-literature