scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Antiviral Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
A Cell ◽  
Aldehyde Groups ◽  
Clinical Potential

ABSTRACTSARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.

scholarly journals In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

2007 ◽  
Vol 51 (4) ◽  
pp. 1440-1445 ◽  
Author(s):  
Shu-Hua Xiao ◽  
Jennifer Keiser ◽  
Jacques Chollet ◽  
Jürg Utzinger ◽  
Yuxiang Dong ◽  
...  
Keyword(s):  
Motor Activity ◽  
Worm Burden ◽  
Female Worm ◽  
Infection Model ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Health Significance ◽  
Low Toxicity

ABSTRACT Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 μg/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

scholarly journals AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2

2020 ◽  
Author(s):  
Bowen Tang ◽  
Fengming He ◽  
Dongpeng Liu ◽  
Meijuan Fang ◽  
Zhen Wu ◽  
...  
Keyword(s):  
Drug Design ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Lead Compounds ◽  
Main Protease ◽  
New Chemical Entities ◽  
Covalent Inhibitors ◽  
Key Enzyme ◽  
Approved Drugs ◽  
Aided Design

AbstractThe focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.

scholarly journals New Potential Drug Candidates Against SARS-CoV-2 Using Generative Model

2021 ◽  
Author(s):  
Madhusudan Verma
Keyword(s):  
Potential Drug ◽  
Q Learning ◽  
Learning Network ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Variational Autoencoder ◽  
New Chemical Entities ◽  
Key Enzyme ◽  
Approved Drugs

<div>Since known approved drugs like liponavir and ritonavir failed to cure SARS-CoV-2 </div><div>infected patients, it is high time to generate new chemical entities against this virus. </div><div>3CL main protease acts as key enzyme for the growth of a virus which acts as </div><div>biocatalyst and helps to break protein and ultimately in the growth of coronavirus. </div><div>Based on a recently solved structure (PDB ID: 6LU7), we developed a novel </div><div>advanced deep Q-learning network with the fragment-based drug design </div><div>(ADQN-FBDD) along with variational autoencoder with KL annealing and circular </div><div>annealing for generating potential lead compounds targeting SARS-CoV-2 3CLpro. </div><div>Structure-based optimization policy (SBOP) is used in reinforcement learning. The </div><div>reason for using variational autoencoders is that it does not deviate much from actual </div><div>inhibitors, but since VAE suffers from KL diminishing we have used KL annealing </div><div>and circular annealing to address this issue. Researchers can use this compound as </div><div>potential drugs against SARS-CoV-2</div>

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

scholarly journals Medicinal Utility of Some Schiff Bases and their Complexes with First Transition Series Metals: A Review

2021 ◽  
Vol 37 (5) ◽  
pp. 1051-1061
Author(s):  
Tahmeena Khan ◽  
Saima Zehra ◽  
Almas Alvi ◽  
Umama Fatima ◽  
Alfred J. Lawrence
Keyword(s):  
Transition Metal ◽  
Metal Complexes ◽  
Transition Metal Complexes ◽  
Present Review ◽  
Potential Drug ◽  
Drug Candidates ◽  
Transition Series ◽  
Low Toxicity ◽  
Activity Enhancement

Schiff based ligands and their complexes have emerged as potential drug candidates. Owing to their excellent chelating tendency, they easily coordinate with transition metals which have vacant orbitals. Transition metal complexes have several advantages because of their better acceptability and low toxicity in biological systems. These metals also serve as micronutrients and as co-factors of various metallo-enzymes which justifies the need of their designing and synthesis. Many modifications have been suggested in the ligand moiety for the purpose of activity enhancement and some of them have been described in the present review. These modifications have enhanced better potency against a number of diseases and resulting in low toxicity and better solubility in vivo. The transition metal complexes with Schiff based complexes have exhibited an array of activities including anticancer, antioxidant and antimicrobial. Their analytical applications have also been reported. The present review summarizes some of the recent advances in the field of synthesis and designing of new Schiff based complexes particularly with first transition series metals and their medicinal applications.

scholarly journals X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

2020 ◽  
Author(s):  
Linlin Zhang ◽  
Daizong Lin ◽  
Xinyuanyuan Sun ◽  
Katharina Rox ◽  
Rolf Hilgenfeld
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Atypical Pneumonia ◽  
The Novel ◽  
Replication Complex ◽  
X Ray ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Novel Coronavirus ◽  
Further Development

AbstractA novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

scholarly journals Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

2020 ◽  
Author(s):  
pooja singh ◽  
Angkita Sharma ◽  
Shoma Paul Nandi
Keyword(s):  
Molecular Docking ◽  
Antiviral Drug ◽  
Cyclopiazonic Acid ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Docking Score ◽  
Protease Enzyme ◽  
Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

scholarly journals The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

2021 ◽  
Vol 22 (19) ◽  
pp. 10773
Author(s):  
Sylwia Sudoł ◽  
Agnieszka Cios ◽  
Magdalena Jastrzębska-Więsek ◽  
Ewelina Honkisz-Orzechowska ◽  
Barbara Mordyl ◽  
...  
Keyword(s):  
Therapeutic Approach ◽  
Cognitive Disorders ◽  
Drug Candidates ◽  
Piperazine Derivatives ◽  
Pharmacokinetic Properties ◽  
Chemical Class ◽  
Novel Therapeutic ◽  
Dementia Diseases

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor.. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

scholarly journals A computational biology approach for the identification of potential SARS-CoV-2 main protease inhibitors from natural essential oil compounds.

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1313
Author(s):  
Rizone Al Hasib ◽  
Md. Chayan Ali ◽  
Md. Shahedur Rahman ◽  
Md. Mafizur Rahman ◽  
Fee Faysal Ahmed ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Essential Oil ◽  
New Drugs ◽  
Dynamics Simulation ◽  
World Health ◽  
Drug Candidates ◽  
Main Protease ◽  
Essential Oil Compounds

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fomented a climate of fear worldwide due to its rapidly spreading nature, and high mortality rate. The World Health Organization (WHO) declared it as a global pandemic on 11th March, 2020. Many endeavors have been made to find appropriate medications to restrain the SARS CoV-2 infection from spreading but there is no specific antiviral therapy to date. However, a computer-aided drug design approach can be an alternative to identify probable drug candidates within a short time. SARS-CoV-2 main protease is a proven drug target, and it plays a pivotal role in viral replication and transcription. Methods: In this study, we identified a total of 114 essential oil compounds as a feasible anti-SARS-CoV-2 agent from several online reservoirs. These compounds were screened by incorporating ADMET profiling, molecular docking, and 50 ns of molecular dynamics simulation to identify potential drug candidates against the SARS-CoV-2 main protease. The crystallized SARS-CoV-2 main protease structure was collected from the RCSB PDB database (PDB ID 6LU7). Results: According to the results of the ADMET study, none of the compounds have any side effects that could reduce their druglikeness or pharmacokinetic properties. Out of 114 compounds, we selected bisabololoxide B, eremanthin, and leptospermone as our top drug candidates based on their higher binding affinity scores, and strong interaction with the Cys 145-His 41 catalytic dyad. Finally, the molecular dynamics simulation was implemented to evaluate the structural stability of the ligand-receptor complex. MD simulations disclosed that all the hits showed conformational stability compared to the positive control α-ketoamide. Conclusions: Our study showed that the top three hits might work as potential anti-SARS-CoV-2 agents, which can pave the way for discovering new drugs, but for experimental validation, they will require more in vivo trials.

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