Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV-2 Non-Structural Proteins Implicated in Viral Pathogenesis

Background: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease (nsp3), 3-chymotrypsin-like protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13), SAM-dependent 2’-O-methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity was also determined using OSIRIS Property Explorer. Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (1), robustaflavone (4), punicalin (9), volkensiflavone (11), rhusflavanone (13), morelloflavone (14), hinokiflavone (15), and michellamine B (19) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (2), pomolic acid (5), ursolic acid (10), garcisaterpenes A (12), hinokiflavone (15), and digitoxigenin-3-O-glucoside (17) were computationally druggable. Moreover, compounds 5 and 17 showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic. Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti-COVID-19 drug design.

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Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV-2 Non-Structural Proteins Implicated in Viral Pathogenesis

10.26434/chemrxiv.14125433 ◽

2021 ◽

Author(s):

Von Novi de Leon ◽

Joe Anthony Manzano ◽

Delfin Yñigo H. Pilapil ◽

Rey Arturo T. Fernandez ◽

James Kyle Ching ◽

...

Keyword(s):

In Silico ◽

Structural Proteins ◽

Treatment Gap ◽

Hiv Reverse Transcriptase ◽

Pomolic Acid ◽

Absorptive Property ◽

Hiv Rt ◽

Key Sites ◽

Inhibitory Potential ◽

Anti Hiv

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Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00206-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Von Novi O. de Leon ◽

Joe Anthony H. Manzano ◽

Delfin Yñigo H. Pilapil ◽

Rey Arturo T. Fernandez ◽

James Kyle Anthony R. Ching ◽

...

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Reverse Transcriptase ◽

In Silico ◽

Structural Proteins ◽

Hiv Reverse Transcriptase ◽

Catalytic Sites ◽

Key Sites ◽

Inhibitory Potential ◽

Anti Hiv

Abstract Background Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. This study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. One hundred four anti-HIV phytochemicals were subjected to molecular docking with nsp3, 5, 10, 12, 13, 15, and 16. Top compounds in complex with the nsps were investigated further through molecular dynamics. The drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top compounds were also predicted using SwissADME. Their toxicity was likewise determined using OSIRIS Property Explorer. Results Among the top-scoring compounds, the polyphenolic functionalized natural products comprised of biflavones 1, 4, 11, 13, 14, 15; ellagitannin 9; and bisisoquinoline alkaloid 19 were multi-targeting and exhibited strongest binding affinities to at least two nsps (binding energy = − 7.7 to − 10.8 kcal/mol). The top ligands were stable in complex with their target nsps as determined by molecular dynamics. Several top-binding compounds were computationally druggable, showed good gastrointestinal absorptive property, and were also predicted to be non-toxic. Conclusions Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 non-structural proteins 3, 5, 10, 12, 13, 15, and 16. Our results highlight the importance of polyhydroxylated aromatic substructures for effective attachment in the binding/catalytic sites of nsps involved in post-translational mechanism pathways. As such with the nsps playing vital roles in viral pathogenesis, our findings provide inspiration for the design and discovery of novel anti-COVID-19 drug prototypes.

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Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

Molecules ◽

10.3390/molecules26133821 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3821

Author(s):

Rita Meleddu ◽

Angela Corona ◽

Simona Distinto ◽

Filippo Cottiglia ◽

Serenella Deplano ◽

...

Keyword(s):

Single Agent ◽

Hiv Reverse Transcriptase ◽

Substitution Pattern ◽

Associated Functions ◽

Dual Inhibition ◽

Hiv Rt ◽

Therapeutic Protocols ◽

Anti Hiv ◽

Hiv 1 ◽

Selection Of

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.

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Screening Inhibitory Potential of Anti-HIV RT RNA Aptamers

Methods in Molecular Biology - Therapeutic Applications of Ribozymes and Riboswitches ◽

10.1007/978-1-62703-730-3_2 ◽

2013 ◽

pp. 11-29 ◽

Cited By ~ 6

Author(s):

Margaret J. Lange ◽

Donald H. Burke

Keyword(s):

Rna Aptamers ◽

Hiv Rt ◽

Inhibitory Potential ◽

Anti Hiv

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The Effect of Absolute Configuration on the Anti-HIV and Anti-HBV Activity of Nucleoside Analogues

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029500600601 ◽

1995 ◽

Vol 6 (6) ◽

pp. 345-355 ◽

Cited By ~ 39

Author(s):

P. A. Furman ◽

J. E. Wilson ◽

J. E. Reardon ◽

G. R. Painter

Keyword(s):

Dna Polymerase ◽

Potent Inhibitor ◽

Hbv Dna ◽

The Other ◽

Nucleoside Analogues ◽

Differential Inhibition ◽

Hiv Reverse Transcriptase ◽

Hiv Rt ◽

Anti Hiv ◽

Selective Activity

This review concerns the effect of stereoisomerism on the selective activity of anti-HIV and anti-HBV nucleoside analogues. The synthesis of a number of nucleoside analogues with anti-HIV and anti-HBV activity yields mixtures of 1-β-D and 1-β-L stereoisomers. Anti-HIV and anti-HBV activity is associated primarily with one of the two enantiomers and the more potent activity does not always reside with the 1-β-D configuration characteristic of natural nucleosides. In the case of HIV, the origin of this stereoselectivity appears to be the result of differential metabolism of the analogues and not due to differential inhibition of the target enzyme; the HIV reverse transcriptase. However, mutations at position 184 of the HIV-RT does result in stereoselective inhibition of the enzyme. On the other hand, with HBV, there is also a stereoselective inhibition of the HBV DNA polymerase, where the 5′-triphosphate of the 1-β-L enantiomer is the more potent inhibitor.

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PASS-based approach to predict HIV-1 reverse transcriptase resistance

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720016500402 ◽

2017 ◽

Vol 15 (02) ◽

pp. 1650040 ◽

Cited By ~ 8

Author(s):

Olga Tarasova ◽

Dmitry Filimonov ◽

Vladimir Poroikov

Keyword(s):

Amino Acid ◽

Reverse Transcriptase ◽

Open Data ◽

Amino Acid Substitutions ◽

Hiv Reverse Transcriptase ◽

Hiv Rt ◽

Hiv Drugs ◽

Rt Inhibitors ◽

Anti Hiv ◽

Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

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Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

Molecules ◽

10.3390/molecules24091718 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1718 ◽

Cited By ~ 4

Author(s):

Roberto Romeo ◽

Daniela Iannazzo ◽

Lucia Veltri ◽

Bartolo Gabriele ◽

Beatrice Macchi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Nucleoside Analogs ◽

Hiv Reverse Transcriptase ◽

Inhibitor Activity ◽

Virus Activity ◽

Immunodeficiency Virus ◽

Hiv Rt ◽

Rt Inhibitors ◽

Anti Hiv ◽

Nanomolar Range

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a–c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

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2,4-Dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic Acid Derivatives: In Vitro Antidiabetic Activity, Molecular Modeling and In silico ADMET Screening

Medicinal Chemistry ◽

10.2174/1573406414666180924164327 ◽

2019 ◽

Vol 15 (2) ◽

pp. 186-195 ◽

Cited By ~ 3

Author(s):

Samridhi Thakral ◽

Vikramjeet Singh

Keyword(s):

Molecular Docking ◽

Benzoic Acid ◽

Inhibitory Activity ◽

In Silico ◽

Computational Study ◽

Antidiabetic Activity ◽

Standard Drug ◽

Benzoic Acid Derivatives ◽

In Silico Admet ◽

Inhibitory Potential

Background: Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in both preventing and treating diabetes. Objective: The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl] benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis. Method: Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds. Results: Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity against α-glucosidase in comparison to standard drug acarbose. Conclusion: Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions.

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Hetero-Tricyclic Lead Scaffold as Novel PDE5A Inhibitor for Antihypertensive Activity: In Silico Docking Studies

Current Computer - Aided Drug Design ◽

10.2174/1573409915666190214161221 ◽

2019 ◽

Vol 15 (4) ◽

pp. 318-333

Author(s):

Dipak P. Mali ◽

Neela M. Bhatia

Keyword(s):

In Silico ◽

Docking Study ◽

Docking Studies ◽

Antihypertensive Activity ◽

In Silico Docking ◽

Π Stacking ◽

Π Stacking Interaction ◽

Nitrogen Heteroatom ◽

Inhibitory Potential ◽

Vlife Mds

Objective:To screen the phytochemicals for phosphodiesterase 5A (PDE5A) inhibitory potential and identify lead scaffolds of antihypertensive phytochemicals using in silico docking studies.Methods:In this perspective, reported 269 antihypertensive phytochemicals were selected. Sildenafil, a PDE5A inhibitor was used as the standard. In silico docking study was carried out to screen and identify the inhibiting potential of the selected phytochemicals against PDE5A enzyme using vLife MDS 4.4 software.Results:Based on docking score, π-stacking, H-bond and ionic interactions, 237 out of 269 molecules were selected which have shown one or more interactions. Protein residue Gln817A was involved in H-boding whereas Val782A, Phe820A and Leu804A were involved in π-stacking interaction with ligand. The selected 237 phytochemicals were structurally diverse, therefore 82 out of 237 molecules with one or more tricycles were filtered out for further analysis. Amongst tricyclic molecules, 14 molecules containing nitrogen heteroatom were selected for lead scaffold identification which finally resulted in three different basic chemical backbones like pyridoindole, tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline as lead scaffolds.Conclusion:In silico docking studies revealed that nitrogen-containing tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline tricyclic lead scaffolds have emerged as novel PDE5A inhibitors for antihypertensive activity. The identified lead scaffolds may provide antihypertensive lead molecules after its optimization.

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