In silico drug repurposing for filarial infection predicts nilotinib and paritaprevir as potential inhibitors of the Wolbachia 5′-aminolevulinic acid synthase

AbstractFilarial infections affect millions of individuals and are responsible for some notorious disabilities. Current treatment options involve repeated mass drug administrations, which have been met with several challenges despite some successes. Administration of doxycycline, an anti-Wolbachia agent, has shown clinical effectiveness but has several limitations, including long treatment durations and contraindications. We describe the use of an in silico drug repurposing approach to screening a library of over 3200 FDA-approved medications against the filarial endosymbiont, Wolbachia. We target the enzyme which catalyzes the first step of heme biosynthesis in the Wolbachia. This presents an opportunity to inhibit heme synthesis, which leads to depriving the filarial worm of heme, resulting in a subsequent macrofilaricidal effect. High throughput virtual screening, molecular docking and molecular simulations with binding energy calculations led to the identification of paritaprevir and nilotinib as potential anti-Wolbachia agents. Having higher binding affinities to the catalytic pocket than the natural substrate, these drugs have the structural potential to bind and engage active site residues of the wolbachia 5′-Aminolevulinic Acid Synthase. We hereby propose paritaprevir and nilotinib for experimental validations as anti-Wolbachia agents.

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Identification of Potential HCV Inhibitors Based on the Interaction of Epigallocatechin-3-Gallate with Viral Envelope Proteins

Molecules ◽

10.3390/molecules26051257 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1257

Author(s):

Fareena Shahid ◽

Noreen ◽

Roshan Ali ◽

Syed Lal Badshah ◽

Syed Babar Jamal ◽

...

Keyword(s):

Hepatitis C ◽

In Silico ◽

Experimental Validation ◽

Homology Modelling ◽

Viral Envelope ◽

Screening Methods ◽

Binding Affinities ◽

Autodock Vina ◽

Potential Inhibitors ◽

Very High

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.

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An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease

Molecular Informatics ◽

10.1002/minf.202000187 ◽

2021 ◽

Author(s):

Nemanja Djokovic ◽

Dusan Ruzic ◽

Teodora Djikic ◽

Sandra Cvijic ◽

Jelisaveta Ignjatovic ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Main Protease ◽

Potential Inhibitors

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In silico screening of W. salutaris bioactive constituents reveal betulinic acid, ursolic acid acetate and eucosterol as potential M. tuberculosis antagonists targeting FabF

10.21203/rs.3.rs-274959/v1 ◽

2021 ◽

Author(s):

Nokukhanya Gumede ◽

Kgothatso E. Machaba ◽

Umar Ndagi ◽

Hezekiel M. Kumalo ◽

Ndumiso N. Mhlongo

Keyword(s):

Ursolic Acid ◽

Betulinic Acid ◽

In Silico ◽

Fatty Acid Biosynthesis ◽

Binding Energies ◽

Active Site Residues ◽

Bioactive Constituents ◽

Inhibitory Potential ◽

Dynamics Simulations ◽

Potential Inhibitors

Abstract Tuberculosis (TB) remains a long-standing burdening disease to control worldwide. The lengthy current TB treatment, which boasts with unbearable adverse effects, and frequent emergence of drug resistant strains of M. tuberculosis lays an increasing burden. This behests urgent discovery and development of alternative novel medicine to alleviate TB. In this report, in silico methods were applied to examine the propensity of W. salutaris active compounds as potential inhibitors of M. tuberculosis fatty acid biosynthesis protein (FabF). Thirteen compounds were virtually screened against FabF and subjected to molecular dynamics simulations and post-dynamics analyses to examine their inhibitory potential. Betulinic acid, ursolic acid and ursolic acid acetate had the best binding energies and hence the best inhibitory potential against FabF and desirable cytotoxicity profile. These compounds bind and interact with FabF active site residues to exert their inhibitory potential. Findings in this preliminary report warrant further experimental validation towards the development of these compounds as potential drugs targeting FabF in the treatment of tuberculosis.

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In Silico Design of Dual-Binding Site Anti-Cholinesterase Phytochemical Heterodimers as Treatment Options for Alzheimer's Disease

Current Issues in Molecular Biology ◽

10.3390/cimb44010012 ◽

2021 ◽

Vol 44 (1) ◽

pp. 152-175

Author(s):

Hafsa Amat-ur-Rasool ◽

Mehboob Ahmed ◽

Shahida Hasnain ◽

Abrar Ahmed ◽

Wayne Grant Carter

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Site ◽

In Silico ◽

Treatment Options ◽

Unmet Need ◽

Drug Efficacy ◽

Huperzine A ◽

Binding Affinities ◽

Number Of Patients

The number of patients with neurodegenerative diseases, particularly Alzheimer’s disease (AD), continues to grow yearly. Cholinesterase inhibitors (ChEIs) represent the first-line symptomatic drug treatment for mild-to-moderate AD; however, there is an unmet need to produce ChEIs with improved efficacy and reduced side effects. Herein, phytochemicals with reported anti-acetylcholinesterase (AChE) activity were ranked in silico for their anti-AChE potential. Ligands with a similar or higher binding affinity to AChE than galantamine were then selected for the design of novel dual-binding site heterodimeric drugs. In silico molecular docking of heterodimers with the target enzymes, AChE and butyrylcholinesterase (BuChE), were performed, and anti-cholinesterase binding affinities were compared with donepezil. Drug-likeliness properties and toxicity of the heterodimers were assessed using the SwissADME and ProTox-II webservers. Nine phytochemicals displayed similar or higher binding affinities to AChE than galantamine: sanguinarine > huperzine A > chelerythrine > yohimbine > berberine > berberastine > naringenin > akuammicine > carvone. Eleven heterodimeric ligands were designed with phytochemicals separated by four- or five-carbon alkyl-linkers. All heterodimers were theoretically potent AChE and BuChE dual-binding site inhibitors, with the highest affinity achieved with huperzine-4C-naringenin, which displayed 34% and 26% improved affinity to AChE and BuChE, respectively, then the potent ChEI drug, donepezil. Computational pharmacokinetic and pharmacodynamic screening suggested that phytochemical heterodimers would display useful gastrointestinal absorption and with relatively low predicted toxicity. Collectively, the present study suggests that phytochemicals could be garnered for the provision of novel ChEIs with enhanced drug efficacy and low toxicity.

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In Silico Screening of Phytochemicals of Ocimum Sanctum Against Main Protease of SARS-CoV-2

10.26434/chemrxiv.12599915.v1 ◽

2020 ◽

Author(s):

Pranab Kishor Mohapatra ◽

Kumar Sambhav Chopdar ◽

Ganesh Chandra Dash ◽

Mukesh Kumar Raval

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Ethanolic Extract ◽

In Silico Analysis ◽

Symptomatic Treatment ◽

Ocimum Sanctum ◽

Aerial Parts ◽

Main Protease ◽

Experimental Validations ◽

Viral Enzyme

<div>COVID19 has compelled the scientific community to search for an effective drug that can cure; a vaccine or an immunity booster that can prevent the disease. As of now, it is tough to discover a new drug and vaccine discovery is even tougher. Drug repurposing is a shortcut to drug discovery for COVID19. Even this has been proved unsatisfactory. Symptomatic treatment and immunity boosters are only alternatives left. Holy Tulsi (Ocimum sanctum) has been known as an ancient remedy for cure of common cold and respiratory ailment in India vis-a-vis also has been prescribed as one of the recommended ingredients in the immunity booster preparations. The ethanolic extract of aerial parts of Tulsi is reported to contain flavonoids and polyphenolic acids, which are also reported earlier to have anti-viral properties experimentally. Therefore, we undertake the in silico analysis of the phytochemicals as inhibitors of main protease of SARS-CoV-2 virus. The result suggests that the flavonoids and polyphenolic compounds of Tulsi, especially luteolin-7-O-glucuronide and chlorogenic acid may covalently bind to the active residue Cys145 of main protease and irreversibly inhibit the viral enzyme. Further experimental validations are required to establish the theoretical findings. <br></div>

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Identification of Antifungal Compounds against Multidrug Resistant Candida auris Utilizing a High Throughput Drug Repurposing Screen

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01305-20 ◽

2021 ◽

Author(s):

Yu-Shan Cheng ◽

Jose Santinni Roma ◽

Min Shen ◽

Caroline Mota Fernandes ◽

Patricia S. Tsang ◽

...

Keyword(s):

High Throughput ◽

High Throughput Screening ◽

Treatment Options ◽

Drug Repurposing ◽

Multidrug Resistant ◽

Current Treatment ◽

Drug Combinations ◽

Serine Palmitoyltransferase ◽

Candida Auris ◽

Pharmacologically Active

Candida auris is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance. Identifying new pharmaceuticals to combat these drug-resistant infections will thus be required to overcome this unmet medical need. We have established a bioluminescent ATP-based assay to identify new compounds and potential drug combinations showing effective growth inhibition against multiple strains of multidrug resistant Candida auris. The assay is robust and suitable for assessing large compound collections by high throughput screening. Utilizing this assay, we conducted a screen of 4,314 approved drugs and pharmacologically active compounds which yielded 25 compounds including 6 novel anti-Candida auris compounds and 13 sets of potential two drug combinations. Among the drug combinations, the serine palmitoyltransferase inhibitor myriocin demonstrated a combinational effect with flucytosine against all tested isolates during screening. This combinational effect was confirmed in 13 clinical isolates of Candida auris.

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Aminoglycosides as potential inhibitors of SARS-CoV-2 main protease: an in silico drug repurposing study on FDA-approved antiviral and anti-infection agents

Journal of Infection and Public Health ◽

10.1016/j.jiph.2021.01.016 ◽

2021 ◽

Vol 14 (5) ◽

pp. 611-619

Author(s):

Mohammad Z. Ahmed ◽

Qamar Zia ◽

Anzarul Haque ◽

Ali S. Alqahtani ◽

Omar M. Almarfadi ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Main Protease ◽

Potential Inhibitors

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Multi-Targeted Approaches and Drug Repurposing Reveal Possible SARS-CoV-2 Inhibitors

Vaccines ◽

10.3390/vaccines10010024 ◽

2021 ◽

Vol 10 (1) ◽

pp. 24

Author(s):

Khalid Mashay Alanazi ◽

Mohammad Abul Farah ◽

Yan-Yan Hor

Keyword(s):

Experimental Validation ◽

Computational Analysis ◽

Treatment Options ◽

Drug Repurposing ◽

Binding Affinities ◽

Normal Model ◽

Inhibitory Potential ◽

Us Fda ◽

Approved Drugs ◽

Fda Approved Drugs

The COVID-19 pandemic caused by SARS-CoV-2 is unprecedented in recent memory owing to the non-stop escalation in number of infections and deaths in almost every country of the world. The lack of treatment options further worsens the scenario, thereby necessitating the exploration of already existing US FDA-approved drugs for their effectiveness against COVID-19. In the present study, we have performed virtual screening of nutraceuticals available from DrugBank against 14 SARS-CoV-2 proteins. Molecular docking identified several inhibitors, two of which, rutin and NADH, displayed strong binding affinities and inhibitory potential against SARS-CoV-2 proteins. Further normal model-based simulations were performed to gain insights into the conformational transitions in proteins induced by the drugs. The computational analysis in the present study paves the way for experimental validation and development of multi-target guided inhibitors to fight COVID-19.

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Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

Pharmaceuticals ◽

10.3390/ph14020087 ◽

2021 ◽

Vol 14 (2) ◽

pp. 87

Author(s):

Andrea Gelemanović ◽

Tinka Vidović ◽

Višnja Stepanić ◽

Katarina Trajković

Keyword(s):

Treatment Options ◽

Drug Repurposing ◽

Enrichment Analysis ◽

Current Treatment ◽

Host Cells ◽

Biological Knowledge ◽

Pathway Enrichment Analysis ◽

Biological Processes ◽

Pathway Enrichment ◽

Drug Candidates

A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID-19.

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Identification of Potential Inhibitors of SARS-CoV-2 Main Protease via a Rapid In-Silico Drug Repurposing Approach

10.26434/chemrxiv.12085083.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Cesar Mendoza-Martinez ◽

Alejandro Rodriguez-Lezama

Keyword(s):

In Silico ◽

Antiviral Agents ◽

Drug Repurposing ◽

Binding Mode ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Binding Modes ◽

Data Set ◽

Main Protease ◽

Potential Inhibitors

An in-silico drug repurposing study was carried out to search for potential COVID-19 antiviral agents. A dataset of 1615 FDA-approved drugs was docked in the active site of SARS CoV-2 Main protease. A subset of the top scoring hit compounds was subjected to follow-up molecular dynamics simulations to further characterise the predicted binding modes. The main findings are that the drugs Aliskiren, Capreomycin, Isovuconazonium, emerge as novel potential inhibitors. We also observed that Ceftolozane, Cobicistat, Carfilzomib and Saquinavir are well-ranked by our protocol, in agreement with other recent in silico drug repurposing studies, however MD simulations shows only potential for the three first, as Saquinavir exhibited an unstable binding mode. As many HIV-protease inhibitors has been reported as active and not active, Atazanavir and Lopinavir were included in the data set in order to rationalize the findings. In addition, our protocol ranked favourably Dronedarone suggesting that this recently reported SARS-CoV-2 inhibitor targets SARS-CoV-2 Main protease.

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