scholarly journals Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase

2021 ◽  
Vol 22 (11) ◽  
pp. 5943
Author(s):  
Alfredo Juárez-Saldivar ◽  
Elizabeth Barbosa-Cabrera ◽  
Edgar E. Lara-Ramírez ◽  
Alma D. Paz-González ◽  
Ana V. Martínez-Vázquez ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Entamoeba Histolytica ◽  
Giardia Lamblia ◽  
Triosephosphate Isomerase ◽  
Glycolytic Enzyme ◽  
Public Health Issue ◽  
Intestinal Protozoan ◽  
Approved Drugs ◽  
Fda Approved Drugs

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05–4.935 μg/mL), while folic acid showed activity against E. histolytica (0.186 μg/mL) and G. lamblia (5.342 μg/mL).

scholarly journals Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

2021 ◽  
Vol 2 (1) ◽  
pp. 16-27
Author(s):  
Zahra Sharifinia ◽  
◽  
Samira Asadi ◽  
Mahyar Irani ◽  
Abdollah Allahverdi ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Angiotensin Converting Enzyme ◽  
Host Cells ◽  
Spike Protein ◽  
Potential Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

scholarly journals Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

2014 ◽  
Vol 58 (12) ◽  
pp. 7072-7082 ◽  
Author(s):  
Horacio Reyes-Vivas ◽  
Ignacio de la Mora-de la Mora ◽  
Adriana Castillo-Villanueva ◽  
Lilian Yépez-Mulia ◽  
Gloria Hernández-Alcántara ◽  
...  
Keyword(s):  
Giardia Lamblia ◽  
Cytotoxic Effect ◽  
Triosephosphate Isomerase ◽  
Glycolytic Enzyme ◽  
Cysteine Residue ◽  
Enzyme Inactivation ◽  
Dependent Manner ◽  
Drug Resistant ◽  
Content Type

ABSTRACTGiardiasis is highly prevalent in the developing world, and treatment failures with the standard drugs are common. This work deals with the proposal of omeprazole as a novel antigiardial drug, focusing on a giardial glycolytic enzyme used to follow the cytotoxic effect at the molecular level. We used recombinant technology and enzyme inactivation to demonstrate the capacity of omeprazole to inactivate giardial triosephosphate isomerase, with no adverse effects on its human counterpart. To establish the specific target in the enzyme, we used single mutants of every cysteine residue in triosephosphate isomerase. The effect on cellular triosephosphate isomerase was evaluated by following the remnant enzyme activity on trophozoites treated with omeprazole. The interaction of omeprazole with giardial proteins was analyzed by fluorescence spectroscopy. The susceptibility to omeprazole of drug-susceptible and drug-resistant strains ofGiardia lambliawas evaluated to demonstrate its potential as a novel antigiardial drug. Our results demonstrate that omeprazole inhibits giardial triosephosphate isomerase in a species-specific manner through interaction with cysteine at position 222. Omeprazole enters the cytoplasmic compartment of the trophozoites and inhibits cellular triosephosphate isomerase activity in a dose-dependent manner. Such inhibition takes place concomitantly with the cytotoxic effect caused by omeprazole on trophozoites.G. lambliatriosephosphate isomerase (GlTIM) is a cytoplasmic protein which can help analyses of how omeprazole works against the proteins of this parasite and in the effort to understand its mechanism of cytotoxicity. Our results demonstrate the mechanism of giardial triosephosphate isomerase inhibition by omeprazole and show that this drug is effectivein vitroagainst drug-resistant and drug-susceptible strains ofG. lamblia.

Selection of Active Antiviral Compounds Against Covid-19 Disease Targeting Coronavirus Endoribonuclease Nendou/NSP15 Via Ligand- Based Virtual Screening and Molecular Docking

2020 ◽  
Vol 17 ◽  
Author(s):  
Gaurav Joshi ◽  
Ramarao Poduri
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Antiviral Compounds ◽  
Clinical Level ◽  
Rapid Spread ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Selection Of

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against Covid-19. Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Results: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against Covid-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against Covid-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CLpro: a study by applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

2022 ◽  
Vol 19 ◽  
Author(s):  
Igor José dos Santos Nascimento ◽  
Thiago Mendonça de Aquino ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
In Silico ◽  
Structural Integrity ◽  
Inhibition Mechanism ◽  
Zinc Database ◽  
Covalent Docking ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Method: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds Result: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His41 and Cys145) and other essential residues for activity (Glu166 and Gln189) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclution: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3461
Author(s):  
Vasiliki Daikopoulou ◽  
Panagiotis Apostolou ◽  
Sofia Mourati ◽  
Ioanna Vlachou ◽  
Maria Gougousi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Drug Repositioning ◽  
Nucleoside Analogues ◽  
In Vitro Assays ◽  
Rna Dependent Rna Polymerase ◽  
Sugar Moiety ◽  
The Family ◽  
Approved Drugs ◽  
Fda Approved Drugs

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.

scholarly journals Inhibición del crecimiento de Giardia Lamblia por acción del extracto acuoso y metanólico de semillas de Cucurbita Pepo / Giardia lamblia growth inhibition by action of the aqueous and methanolic extract of cucurbita pepo seed

2015 ◽  
Vol 1 (1) ◽  
pp. 121
Author(s):  
María Porfiria Barrón González ◽  
Ramón Gerardo Rodríguez Garza ◽  
Yadira Quiñones Gutiérrez
Keyword(s):  
Growth Inhibition ◽  
Entamoeba Histolytica ◽  
Giardia Lamblia ◽  
Cucurbita Pepo ◽  
Methanolic Extract ◽  
Taenia Solium

Giardia lamblia es el protozoario parásito causante de la giardiasis, la cual se caracteriza por molestia abdominal, pérdida de peso y desnutrición. La droga de elección para su tratamiento es el metronidazol sin embargo, presenta diversos efectos secundarios adversos en el paciente. Por otra parte, en la herbolaria se conoce a la semilla de Cucurbita pepo por sus propiedades desparasitante, principalmente sobre Entamoeba histolytica y Taenia solium.  Por lo anterior se planteó la hipótesis de que las semillas de C. pepo contienen principios activos capaces de inhibir el crecimiento de G. lamblia bajo condiciones axénicas in vitro. El objetivo de esta investigación fue evaluar la actividad biológica del extracto acuoso y metanólico de las semillas de  C. pepo sobre el crecimiento de G. lamblia.  Tanto el extracto metanólico como el acuoso se identificaron siete grupos funcionales y la actividad antioxidante no fue significativa. En el extracto metanólico se observó mayor efecto giardicida seguido del acuoso, esta diferencia puede deberse a las saponinas que se encuentran sólo en el extracto metanólico. Los resultados sugieren que las semillas contienen principios activos que pueden emplearse para la investigación de nuevos tratamientos para la  giardiasis.

scholarly journals Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

2018 ◽  
Author(s):  
R. N. V. Krishna Deepak ◽  
Ahmad Abdullah ◽  
Priti Talwar ◽  
Hao Fan ◽  
Palaniyandi Ravanan
Keyword(s):  
Active Site ◽  
Caspase 3 ◽  
Specific Activity ◽  
Special Importance ◽  
Allosteric Inhibitors ◽  
Dimerization Interface ◽  
Executioner Caspases ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractThe regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

scholarly journals Mulberrofuran G, a Potent Inhibitor of SPIKE Protein of SARS Corona Virus 2

2021 ◽  
Author(s):  
Fatemeh Sadat Hosseini ◽  
Mohammad Reza Motamedi
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Active Site ◽  
Potential Role ◽  
Potent Inhibitor ◽  
Screening Method ◽  
Spike Protein ◽  
Treatment Agent ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

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