scholarly journals Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists

2020 ◽  
Author(s):  
Sheng Zhang ◽  
Maj Krumberger ◽  
Michael A. Morris ◽  
Chelsea Marie T. Parrocha ◽  
James H. Griffin ◽  
...  
Keyword(s):  
Drug Design ◽  
Cyclic Peptide ◽  
Free Software ◽  
New Drugs ◽  
Peptide Inhibitor ◽  
Drug Candidate ◽  
Crystallographic Structure ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Main Protease

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (M<sup>pro</sup>) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the M<sup>pro</sup> active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV M<sup>pro</sup> and the highly homologous SARS-CoV-2 M<sup>pro</sup>. The supporting information (supplementary material) provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 M<sup>pro</sup>.

scholarly journals Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists

2020 ◽  
Author(s):  
Sheng Zhang ◽  
Maj Krumberger ◽  
Michael A. Morris ◽  
Chelsea Marie T. Parrocha ◽  
James H. Griffin ◽  
...  
Keyword(s):  
Drug Design ◽  
Cyclic Peptide ◽  
Free Software ◽  
New Drugs ◽  
Peptide Inhibitor ◽  
Drug Candidate ◽  
Crystallographic Structure ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Main Protease

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (M<sup>pro</sup>) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the M<sup>pro</sup> active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV M<sup>pro</sup> and the highly homologous SARS-CoV-2 M<sup>pro</sup>. The supporting information (supplementary material) provides an illustrated step-by-step guide for the inhibitor design, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 M<sup>pro</sup>.

scholarly journals Structure-Based Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease Using Free Software: A Tutorial for Students and Scientists

2020 ◽  
Author(s):  
Sheng Zhang ◽  
Maj Krumberger ◽  
Michael A. Morris ◽  
Chelsea Marie T. Parrocha ◽  
James H. Griffin ◽  
...  
Keyword(s):  
Drug Design ◽  
Cyclic Peptide ◽  
Free Software ◽  
New Drugs ◽  
Peptide Inhibitor ◽  
Drug Candidate ◽  
Crystallographic Structure ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Main Protease

This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (M<sup>pro</sup>) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the M<sup>pro</sup> active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV M<sup>pro</sup> and the highly homologous SARS-CoV-2 M<sup>pro</sup>. The supporting information (supplementary material) provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 M<sup>pro</sup>.

scholarly journals Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice Douangamath ◽  
Daren Fearon ◽  
Paul Gehrtz ◽  
Tobias Krojer ◽  
Petra Lukacik ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Design ◽  
Active Site ◽  
Large Scale ◽  
Structure Based Drug Design ◽  
Dimer Interface ◽  
X Ray ◽  
Fragment Screening ◽  
Viral Proteases ◽  
Main Protease

Abstract COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

scholarly journals Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists

2021 ◽  
Vol 218 ◽  
pp. 113390
Author(s):  
Sheng Zhang ◽  
Maj Krumberger ◽  
Michael A. Morris ◽  
Chelsea Marie T. Parrocha ◽  
Adam G. Kreutzer ◽  
...  
Keyword(s):  
Drug Design ◽  
Free Software ◽  
Structure Based Drug Design ◽  
Main Protease

scholarly journals Near-Physiological-Temperature Serial Femtosecond X-ray Crystallography Reveals Novel Conformations of SARS-CoV-2 Main Protease Active Site for Improved Drug Repurposing

2020 ◽  
Author(s):  
Serdar Durdagi ◽  
Cagdas Dag ◽  
Berna Dogan ◽  
Merve Yigin ◽  
Timucin Avsar ◽  
...  
Keyword(s):  
Drug Design ◽  
Drug Repurposing ◽  
Binding Modes ◽  
Design Studies ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Physiological Temperature ◽  
X Ray Crystallography ◽  
Main Protease ◽  
Molecular Modeling Studies

AbstractThe COVID19 pandemic has resulted in 25+ million reported infections and nearly 850.000 deaths. Research to identify effective therapies for COVID19 includes: i) designing a vaccine as future protection; ii) structure-based drug design; and iii) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determined two apo structures of Severe Acute Respiratory Syndrome CoronaVirus-2 main protease at ambienttemperature by Serial Femtosecond X-ray crystallography. We employed detailed molecular simulations of selected known main protease inhibitors with the structures and compared binding modes and energies. The combined structural biology and molecular modeling studies not only reveal the dynamics of small molecules targeting main protease but will also provide invaluable opportunities for drug repurposing and structure-based drug design studies against SARS-CoV-2.One Sentence SummaryRadiation-damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological-temperature offer invaluable information for immediate drug-repurposing studies for the treatment of COVID19.

scholarly journals Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

2020 ◽  
Author(s):  
Alice Douangamath ◽  
Daren Fearon ◽  
Paul Gehrtz ◽  
Tobias Krojer ◽  
Petra Lukacik ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Design ◽  
Active Site ◽  
Large Scale ◽  
Structure Based Drug Design ◽  
Dimer Interface ◽  
X Ray ◽  
Fragment Screening ◽  
Viral Proteases ◽  
Main Protease

SummaryCOVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

scholarly journals Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design

2014 ◽  
Vol 70 (3) ◽  
pp. 889-903 ◽  
Author(s):  
Alexandra Cousido-Siah ◽  
Francesc X. Ruiz ◽  
André Mitschler ◽  
Sergio Porté ◽  
Ángel R. de Lera ◽  
...  
Keyword(s):  
Drug Design ◽  
Aldose Reductase ◽  
Competitive Inhibition ◽  
Hydroxyl Group ◽  
Crystallographic Structure ◽  
Lysine Methylation ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Inhibitor Selectivity

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer,e.g.hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50values of both AKRs with a series of polyhalogenated compounds, 2,2′,3,3′,5,5′,6,6′-octafluoro-4,4′-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1′-biphenyl-4,4′-diol). An ultrahigh-resolution X-ray structure of the AR–NADP+–JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e.the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10–NADP+–JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

scholarly journals Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jérémie Piton ◽  
Anthony Vocat ◽  
Andréanne Lupien ◽  
Caroline S. Foo ◽  
Olga Riabova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Antitubercular Activity ◽  
Cysteine Residue ◽  
Drug Candidate ◽  
Structure Based Drug Design ◽  
Content Type ◽  
Active Site Cysteine ◽  
Covalent Adducts

ABSTRACT Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

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