scholarly journals In Silico Identification of the Potential Natural Inhibitors of SARS-CoV-2 Guanine-N7 Methyltransferase.

2020 ◽  
Author(s):  
adekunle rowaiye ◽  
Olukemi Onuh ◽  
Joy Awulika Oladimeji-Salami ◽  
Doofan Bur ◽  
Moses Njoku ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Lead Compounds ◽  
Cellular Defense ◽  
Pharmacokinetic Properties ◽  
The Galaxy ◽  
African Plants ◽  
Oral Availability ◽  
Important Physiological Process ◽  
Natural Inhibitors ◽  
Important Enzyme

The outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 has triggered intense scientific research into the possible therapeutic strategies that can combat the ravaging disease. One of such strategies is the inhibition of an important enzyme that affects an important physiological process of the virus. The enzyme, Guanine 7 Methyltransferase is responsible for the capping of the SARS-CoV-2 mRNA to conceal it from the host’s cellular defense. The study aims at computationally identifying the potential natural inhibitors of the SARS-CoV-2 GuanineN7 methyltransferase binding at the active site (Pocket 41). A library of small molecules was obtained from edible African plants and were molecularly docked against the SARS-CoV-2 Guanine-N7 methyltransferase (QHD43415_13. pdb) using the Pyrx software. Sinefungin, an approved antiviral drug which had a binding score of -7.6 kcal/ mol with the target was chosen as a standard. Using the molecular descriptors of the compounds, a virtual screening for oral availability was performed using the Pubchem and SWISSADME web tools. The online servers PKCSM and Molinspiration were used for further screening for pharmacokinetic properties and bioactivity respectively. The molecular dynamic simulation and analyses of the Apo and Holo proteins was performed using the GROMACS software on the Galaxy webserver. The lead compounds are Crinamidine, Marmesin and Sinensetin which are obtained from waterleaf, mango, and orange plants respectively. All the lead compounds performed better than the standard. Crinamidine is predicted to show the greatest inhibitory activity. Further tests are required to further investigate the inhibitory activities of the lead compounds.

scholarly journals In Silico Identification of the Potential Natural Inhibitors of SARS-CoV-2 Guanine-N7 Methyltransferase.

2020 ◽  
Author(s):  
adekunle rowaiye ◽  
Olukemi Onuh ◽  
Joy Awulika Oladimeji-Salami ◽  
Doofan Bur ◽  
Moses Njoku ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Lead Compounds ◽  
Cellular Defense ◽  
Pharmacokinetic Properties ◽  
The Galaxy ◽  
African Plants ◽  
Oral Availability ◽  
Important Physiological Process ◽  
Natural Inhibitors ◽  
Important Enzyme

The outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 has triggered intense scientific research into the possible therapeutic strategies that can combat the ravaging disease. One of such strategies is the inhibition of an important enzyme that affects an important physiological process of the virus. The enzyme, Guanine 7 Methyltransferase is responsible for the capping of the SARS-CoV-2 mRNA to conceal it from the host’s cellular defense. The study aims at computationally identifying the potential natural inhibitors of the SARS-CoV-2 GuanineN7 methyltransferase binding at the active site (Pocket 41). A library of small molecules was obtained from edible African plants and were molecularly docked against the SARS-CoV-2 Guanine-N7 methyltransferase (QHD43415_13. pdb) using the Pyrx software. Sinefungin, an approved antiviral drug which had a binding score of -7.6 kcal/ mol with the target was chosen as a standard. Using the molecular descriptors of the compounds, a virtual screening for oral availability was performed using the Pubchem and SWISSADME web tools. The online servers PKCSM and Molinspiration were used for further screening for pharmacokinetic properties and bioactivity respectively. The molecular dynamic simulation and analyses of the Apo and Holo proteins was performed using the GROMACS software on the Galaxy webserver. The lead compounds are Crinamidine, Marmesin and Sinensetin which are obtained from waterleaf, mango, and orange plants respectively. All the lead compounds performed better than the standard. Crinamidine is predicted to show the greatest inhibitory activity. Further tests are required to further investigate the inhibitory activities of the lead compounds.

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 In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2 Helicase

2020 ◽  
Author(s):  
Adekunle Rowaiye ◽  
Olukemi Onuh ◽  
Titilayo Asala ◽  
Amoge Ogu ◽  
Doofan Bur ◽  
...  
Keyword(s):  
Small Molecules ◽  
Inhibitory Activity ◽  
In Silico ◽  
Allosteric Site ◽  
Allosteric Inhibitors ◽  
Protein Targets ◽  
Docking Simulations ◽  
Lead Compounds ◽  
The Galaxy ◽  
African Plants

<p>The COVID-19 pandemic ravages the globe causing unprecedented health and economic challenges. As the world prospects for a cure, scientists are looking critically at strategic protein targets within the SARS-CoV-2 that have therapeutic significance. One of such targets is the Helicase which is an enzyme that affects all aspects of SARS-CoV-2 RNA metabolism. The aim of this study is to identify small molecules from natural products that have strong binding affinity with and inhibitory activity against an allosteric site (Pocket 26) of SARS-CoV-2 Helicase. Pyrx was used for the <i>in silico</i> molecular docking simulations of SARS-CoV-2 Helicase (QHD43415-12.pdb) against a library of small molecules obtained from edible African plants. Triphenylmethane which had a docking score of -7.4 kcal/mol was chosen as a reference molecule. Virtual screening for oral bioavailability was done based on the molecular descriptors of the compounds as provided by Pubchem. SwissADME, pkCSM, and Molinspiration were used for further screening for molar refractivity, saturation, promiscuity, pharmacokinetic properties, and bioactivity respectively. The Galaxy webserver which uses the GROMACS software was used for the molecular dynamic simulation and analyses. The lead compounds are Gibberellin A12, A20 and A51 obtained from Green peas and the Okra plant. <a>Gibberellin A20 and A51 </a>performed better than the standard. Gibberellin A51 is predicted to show the greatest inhibitory activity against SARS-CoV-2 Helicase. It is recommended that the inhibitory activities of the lead compounds be further investigated.</p>

scholarly journals In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2 Helicase

2020 ◽  
Author(s):  
Adekunle Rowaiye ◽  
Olukemi Onuh ◽  
Titilayo Asala ◽  
Amoge Ogu ◽  
Doofan Bur ◽  
...  
Keyword(s):  
Small Molecules ◽  
Inhibitory Activity ◽  
In Silico ◽  
Allosteric Site ◽  
Allosteric Inhibitors ◽  
Protein Targets ◽  
Docking Simulations ◽  
Lead Compounds ◽  
The Galaxy ◽  
African Plants

<p>The COVID-19 pandemic ravages the globe causing unprecedented health and economic challenges. As the world prospects for a cure, scientists are looking critically at strategic protein targets within the SARS-CoV-2 that have therapeutic significance. One of such targets is the Helicase which is an enzyme that affects all aspects of SARS-CoV-2 RNA metabolism. The aim of this study is to identify small molecules from natural products that have strong binding affinity with and inhibitory activity against an allosteric site (Pocket 26) of SARS-CoV-2 Helicase. Pyrx was used for the <i>in silico</i> molecular docking simulations of SARS-CoV-2 Helicase (QHD43415-12.pdb) against a library of small molecules obtained from edible African plants. Triphenylmethane which had a docking score of -7.4 kcal/mol was chosen as a reference molecule. Virtual screening for oral bioavailability was done based on the molecular descriptors of the compounds as provided by Pubchem. SwissADME, pkCSM, and Molinspiration were used for further screening for molar refractivity, saturation, promiscuity, pharmacokinetic properties, and bioactivity respectively. The Galaxy webserver which uses the GROMACS software was used for the molecular dynamic simulation and analyses. The lead compounds are Gibberellin A12, A20 and A51 obtained from Green peas and the Okra plant. <a>Gibberellin A20 and A51 </a>performed better than the standard. Gibberellin A51 is predicted to show the greatest inhibitory activity against SARS-CoV-2 Helicase. It is recommended that the inhibitory activities of the lead compounds be further investigated.</p>

scholarly journals In Silico Identification of Potential Allosteric Inhibitors of the SARS-CoV-2 Helicase

2020 ◽  
Author(s):  
Adekunle Rowaiye ◽  
Olukemi Onuh ◽  
Titilayo Asala ◽  
Amoge Ogu ◽  
Doofan Bur ◽  
...  
Keyword(s):  
Small Molecules ◽  
Inhibitory Activity ◽  
In Silico ◽  
Allosteric Site ◽  
Allosteric Inhibitors ◽  
Protein Targets ◽  
Docking Simulations ◽  
Lead Compounds ◽  
The Galaxy ◽  
African Plants

<p>The COVID-19 pandemic ravages the globe causing unprecedented health and economic challenges. As the world prospects for a cure, scientists are looking critically at strategic protein targets within the SARS-CoV-2 that have therapeutic significance. One of such targets is the Helicase which is an enzyme that affects all aspects of SARS-CoV-2 RNA metabolism. The aim of this study is to identify small molecules from natural products that have strong binding affinity with and inhibitory activity against an allosteric site (Pocket 26) of SARS-CoV-2 Helicase. Pyrx was used for the <i>in silico</i> molecular docking simulations of SARS-CoV-2 Helicase (QHD43415-12.pdb) against a library of small molecules obtained from edible African plants. Triphenylmethane which had a docking score of -7.4 kcal/mol was chosen as a reference molecule. Virtual screening for oral bioavailability was done based on the molecular descriptors of the compounds as provided by Pubchem. SwissADME, pkCSM, and Molinspiration were used for further screening for molar refractivity, saturation, promiscuity, pharmacokinetic properties, and bioactivity respectively. The Galaxy webserver which uses the GROMACS software was used for the molecular dynamic simulation and analyses. The lead compounds are Gibberellin A12, A20 and A51 obtained from Green peas and the Okra plant. <a>Gibberellin A20 and A51 </a>performed better than the standard. Gibberellin A51 is predicted to show the greatest inhibitory activity against SARS-CoV-2 Helicase. It is recommended that the inhibitory activities of the lead compounds be further investigated.</p>

scholarly journals Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family

2011 ◽  
Vol 55 (5) ◽  
pp. 1975-1981 ◽  
Author(s):  
Matthew A. Gregory ◽  
Michael Bobardt ◽  
Susan Obeid ◽  
Udayan Chatterji ◽  
Nigel J. Coates ◽  
...  
Keyword(s):  
Large Scale ◽  
Scale Production ◽  
Subgenomic Replicon ◽  
Isomerase Activity ◽  
Lead Compounds ◽  
Naturally Occurring ◽  
Large Scale Production ◽  
Pharmacokinetic Properties ◽  
Biosynthetic Engineering

ABSTRACTCyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F< 4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2> 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.

scholarly journals In silico model and design of novel 5α-reductase inhibitors for treatment of benign prostatic hyperplasia

2021 ◽  
Vol 18 (10) ◽  
pp. 2081-2088
Author(s):  
Qi Lin ◽  
Danhua Lin ◽  
Ying Zhang
Keyword(s):  
In Silico ◽  
Docking Simulation ◽  
Prostate Hyperplasia ◽  
Online Programs ◽  
Lead Compounds ◽  
Reductase Inhibitors ◽  
Potent Inhibition ◽  
Simulation Based ◽  
Pharmacokinetic Properties ◽  
In Silico Molecular Docking

Purpose: To carry out in silico design of 5α-reductase inhibitors and study their potential for use in the treatment of benign prostate hyperplasia (BPH). Methods: In silico molecular docking simulation-based virtual screening of NCI Diversity Set-II containing 1880 diverse ligands was performed against human 5α-reductase for identification of potential lead molecules. The pharmacological properties and toxicity of the lead compounds were determined using software, Marvin Sketch and OSIRIS online programs, respectively. Results: Three compounds: ZINC13099050, ZINC01569237 and ZINC17995347_2 showed potent inhibition of 5α-reductase enzyme protein and good pharmacokinetic properties without any serious toxic effects. Conclusion: The selected lead molecules are promising inhibitors of 5α-reductase. They are recommended for further structure-based development of drugs for the treatment of BPH.

scholarly journals 2-Amino-1,3,4-thiadiazoles as prospective agents in trypanosomiasis and other parasitoses

2020 ◽  
Vol 70 (3) ◽  
pp. 259-290 ◽  
Author(s):  
Georgeta Serban
Keyword(s):  
Public Health Problem ◽  
Parasitic Infections ◽  
Lead Compounds ◽  
New Class ◽  
Pharmacokinetic Properties ◽  
Scientific Papers ◽  
Thiadiazole Ring ◽  
Drug Synthesis ◽  
Antiparasitic Drugs

AbstractParasitic diseases are a serious public health problem affecting hundreds of millions of people worldwide. African trypanosomiasis, American trypanosomiasis, leishmaniasis, malaria and toxoplasmosis are the main parasitic infections caused by protozoan parasites with over one million deaths each year. Due to old medications and drug resistance worldwide, there is an urgent need for new antiparasitic drugs. 1,3,4-Thiadiazoles have been widely studied for medical applications. The chemical, physical and pharmacokinetic properties recommend 1,3,4-thiadiazole ring as a target in drug development. Many scientific papers report the antiparasitic potential of 2-amino-1,3,4-thiadiazoles. This review presents synthetic 2-amino-1,3,4-thiadiazoles exhibiting antitrypanosomal, antimalarial and antitoxoplasmal activities. Although there are insufficient results to state the quality of 2-amino-1,3,4-thiadiazoles as a new class of antiparasitic agents, many reported derivatives can be considered as lead compounds for drug synthesis and a promise for the future treatment of parasitosis and provide a valid strategy for the development of potent antiparasitic drugs.

scholarly journals The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses

2020 ◽  
Vol 117 (48) ◽  
pp. 30687-30698
Author(s):  
Stuart Weston ◽  
Lauren Baracco ◽  
Chloe Keller ◽  
Krystal Matthews ◽  
Marisa E. McGrath ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Drug Target ◽  
Influenza A ◽  
Genetic Interaction ◽  
Antiviral Drug ◽  
Binding Pocket ◽  
Potential Host ◽  
Lead Compounds ◽  
Chemical Structures ◽  
In Silico Modeling

The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.

scholarly journals Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 661 ◽  
Author(s):  
Venugopala ◽  
Al-Attraqchi ◽  
Tratrat ◽  
Nayak ◽  
Morsy ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Agents ◽  
Cox Inhibitors ◽  
Lead Compounds ◽  
Important Target ◽  
Pharmacokinetic Properties ◽  
Molecular Modeling Studies ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 2 Inhibitors

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

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