scholarly journals Revealing Potential Binding Affinity of FDA Approved Therapeutics Targeting Main Protease (3CLpro) in Impairing Novel Coronavirus (SARSCoV- 2) Replication that Causes COVID-19

Coronaviruses ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 98-107
Author(s):  
D. Sivaraman ◽  
P.S. Pradeep ◽  
S. Sundar Manoharan ◽  
C. Ramachandra Bhat ◽  
K.V. Leela ◽  
...  
Keyword(s):  
Viral Replication ◽  
Enzyme Inhibitors ◽  
Binding Capacity ◽  
Biological Significance ◽  
Docking Simulation ◽  
Biologically Active ◽  
Helical Chain ◽  
Drug Of Choice ◽  
Novel Coronavirus ◽  
Approved Drugs

Background: Spread of COVID-19 attains a crucial transition in reveling its pandemic across the boundaries. In combating the infection caused by SARS-CoV-2, there is a spectrum of ideal strategies that have been adopted globally, of which repurposing of approved drugs considerably having high clinical relevance. 3-chymotrypsin-like protease (3CL pro) is considered to be the potential target for the researchers as it is highly essential for cleavage of polyprotein to get 16 nonstructural proteins (called nsp1-nsp16). These proteins are highly essential for viral replication and hence become a primary target for enzyme inhibitors. 3CL pro, having a structural projectile helical chain with biologically active site involved in processing viral polyproteins that are evolved from RNA genome translation. Objective: The major objective of the present investigation is to evaluate the enzyme inhibition potential of FDA approved therapeutic leads in targeting 3CLpro that medicates the viral replication. Methods: Docking calculations were carried out for an array of FDA approved molecules which leads to a notable few molecules such as Emtricitabine, Oseltamivir, Ganciclovir, Chloroquine, Baricitinib, Favipiravir, Lopinavir, Ritonavir, Remdesivir, Ribavirin, Tenofovir, Umifenovir, Carbapenam, Ertapenem and Imipenam which have both specificity and selectivity in terms of binding efficiency against 3CL proenzyme. Results: A combinatorial evaluation employing in-silico screening shows a major lead for remdesivir which possesses a substantial affinity to 3CL pro binding on core amino acid residues, such as Leu 27, His 41, Gly 143, Cys 145, His 164, Met 165, Glu 166, Pro 168 and His 172 which share the biological significance in mediating enzymatic action. Results of docking simulation by Autodock over a host of FDA approved molecules show high degree of selectivity and specificity in the increasing order of binding capacity; Remdesivir> Ertapenem> Imipenam> Tenofovir> Umifenovir> Chloroquine> Lopinavir> Ritonavir> Emtricitabine> Ganciclovir> Baricitinib> Ribavirin>Oseltamivir>Favipiravir> Carbapenam. Conclusion: Till date, there is no known cure attained for treating COVID-19 infection. In conclusion, lead molecules from already approved sources provoke promising potential which grabs the attention of the clinicians in availing potential therapeutic candidate as a drug of choice in the clinical management of COVID-19 time-dependently.

PLASMA CORTISOL, CORTICOSTERONE AND NON-PROTEIN-BOUND CORTISOL IN EXTRACORPOREAL CIRCULATION

1972 ◽  
Vol 69 (3) ◽  
pp. 517-525 ◽  
Author(s):  
T. Uozumi ◽  
H. Manabe ◽  
Y. Kawashima ◽  
Y. Hamanaka ◽  
Y. Monden ◽  
...  
Keyword(s):  
Cortisol Level ◽  
Extracorporeal Circulation ◽  
Plasma Cortisol ◽  
Elevated Level ◽  
Marked Decrease ◽  
Binding Capacity ◽  
Biologically Active ◽  
Major Surgery ◽  
Plasma Samples ◽  
Effective Factor

ABSTRACT The response of plasma cortisol, corticosterone and non-protein-bound cortisol in the extracorporeal circulation was investigated in 14 patients. The pre-perfusion levels of plasma cortisol, corticosterone and non-protein-bound cortisol were significantly elevated. During and immediately after perfusion, the levels of cortisol and corticosterone were found to decrease significantly from the pre-perfusion levels, while the percentage of non-protein-bound cortisol was shown to increase significantly. This indicates a marked decrease in cortisol binding capacity of plasma during extracorporeal circulation. Moreover in 200 plasma samples, it was demonstrated that the cortisol level increased markedly and the cortisol binding capacity decreased slightly during and shortly after major surgery without perfusion. It is concluded that stressful situations in major surgery with or without perfusion are associated with markedly increased levels of biologically active non-protein-bound cortisol. The elevated level of non-protein-bound cortisol in surgery seems to be dependent on the increase in the level of plasma cortisol as well as on the decrease in the cortisol binding capacity of plasma. Although the increased plasma cortisol plays the most important role in surgery with no perfusion, the decreased cortisol binding capacity may be the more effective factor involved during perfusion.

Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

2018 ◽  
Vol 15 (2) ◽  
pp. 208-220 ◽  
Author(s):  
Vaibhav Mishra ◽  
Tejpal Singh Chundawat
Keyword(s):  
Bond Formation ◽  
Catalyst Design ◽  
Biologically Active ◽  
Reaction Conditions ◽  
Biological Targets ◽  
Amination Reaction ◽  
Drug Synthesis ◽  
Substituted Piperazine ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Arash Soltani ◽  
Seyed Isaac Hashemy ◽  
Farnaz Zahedi Avval ◽  
Houshang Rafatpanah ◽  
Seyed Abdolrahim Rezaee ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Capacity ◽  
Binding Pocket ◽  
Ligand Docking ◽  
Binding Modes ◽  
Wild Type ◽  
Parent Molecule ◽  
Discovery Studio ◽  
Approved Drugs ◽  
Hiv 1

Introoduction: Inhibition of the reverse transcriptase (RT) enzyme of human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed. Methods: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. Then the parent molecule and derivatives were docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in druglikeness screening by Swiss-ADME or in docking stage. Results: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to -58.3 and -54.5 KJ/mol, respectively. Conclusion: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using fragment-based approach.

scholarly journals Thiazole Ring—A Biologically Active Scaffold

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3166
Author(s):  
Anthi Petrou ◽  
Maria Fesatidou ◽  
Athina Geronikaki
Keyword(s):  
Recent Literature ◽  
Biological Activities ◽  
Literature Survey ◽  
Biologically Active ◽  
Thiazole Ring ◽  
Peer Reviews ◽  
Experimental Drugs ◽  
Wide Range ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. Objective: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. Results: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.

scholarly journals Potential 2019-nCoV 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches

2020 ◽  
Author(s):  
Alex Zhavoronkov ◽  
Vladimir Aladinskiy ◽  
Alexander Zhebrak ◽  
Bogdan Zagribelnyy ◽  
Victor Terentiev ◽  
...  
Keyword(s):  
Homology Modelling ◽  
Drug Repurposing ◽  
Hiv Protease ◽  
Learning Approaches ◽  
Protein Targets ◽  
Chemical Libraries ◽  
Internal Resources ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Novel Drug

<div> <div> <div> <p>The emergence of the 2019 novel coronavirus (2019-nCoV), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important 2019-nCoV protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of 2019-nCoV and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked- based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches are being published at www.insilico.com/ncov-sprint/ and will be continuously updated. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. </p> </div> </div> </div>

scholarly journals Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening

2020 ◽  
Author(s):  
Yan Li ◽  
Jinyong Zhang ◽  
Ning Wang ◽  
Haibo Li ◽  
Yun Shi ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Binding Capacity ◽  
Effective Means ◽  
Clinical Applications ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Clinical Drug ◽  
Specific Inhibitors

Abstract2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.

scholarly journals RECENTES AVANÇOS NA FUNCIONALIZAÇÃO SELETIVA DE QUINOLINAS

Química Nova ◽  
2021 ◽  
Author(s):  
Dartagnan Ferreira ◽  
Valter Murie ◽  
Thiago Santos ◽  
Paulo Vieira ◽  
Giuliano Clososki
Keyword(s):  
Wide Spectrum ◽  
Structural Diversity ◽  
Biological Properties ◽  
Biologically Active ◽  
Chemical Transformations ◽  
Heterocyclic Molecules ◽  
Point Of Interest ◽  
Selective Functionalization ◽  
Biological Interest ◽  
Approved Drugs

RECENT ADVANCES IN SELECTIVE FUNCTIONALIZATION OF QUINOLINES. Heterocyclic compounds form an important and extensive group of organic substances. Among nitrogenous heterocyclic molecules, quinolines stand out for exhibiting attractive chemical and biological properties. These substances can be used as ligands, sensors, luminescent and agrochemical materials. In addition, quinoline-containing compounds can exhibit a wide spectrum of pharmacological properties, allowing their use in several approved drugs nowadays. Due to its importance, the synthesis of molecules containing this nucleus becomes a point of interest for synthetic chemists. In this way, several methodologies have been recently developed to prepare quinoline derivatives with high structural diversity. Such chemical transformations allow the chemical modification of these rings with high selectivity and tolerance to diverse functional groups and these properties have been conveniently used in the preparation of biologically active molecules containing this unit. Herein, we present a review of the main methodologies employed in the selective functionalization of quinolines in the last twenty years. In this context, a brief introduction addressing general synthetic and medicinal aspects related to the functionalization positions of the quinoline ring is presented. Several methodologies used in the functionalization of this moiety are discussed, as well relevant synthetic applications, both in the preparation and functionalization of substances of biological interest.

scholarly journals Responses of New World flying squirrels to the acute stress of capture and handling

2015 ◽  
Vol 97 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Lanna M. Desantis ◽  
Jeff Bowman ◽  
Candace V. Lahoda ◽  
Rudy Boonstra ◽  
Gary Burness
Keyword(s):  
Stress Response ◽  
New World ◽  
Binding Capacity ◽  
Biologically Active ◽  
Stress Axis ◽  
Neutrophil Lymphocyte Ratio ◽  
Flying Squirrels ◽  
Physiological Variables ◽  
Total Cortisol ◽  
Cortisol Levels

Abstract Northern ( Glaucomys sabrinus ) and southern ( G. volans ) flying squirrels have glucocorticoid (GC; stress hormone) levels higher than most vertebrates but virtually no binding capacity for these GCs via the carrier protein, corticosteroid-binding globulin. Thus, their total GCs are essentially all free and biologically active. However, the GC estimates come from blood samples taken after squirrels had been in live traps, and thus in a stress-induced state. Obtaining baseline values for physiological variables is valuable for assessing the response of vertebrates to stressors in their environment. We compared baseline plasma total cortisol levels (within 3min of capture) to stress-induced levels (after 30min of trap restraint) in both flying squirrel species. We recorded baseline cortisol levels that were some of the highest ever reported for mammals, indicating their stress axes operate at a higher set point than most other species. As part of the stress response, we also measured 4 indices in addition to cortisol. Total cortisol and free fatty acids increased in both species, as predicted. In contrast with our predictions, blood glucose and neutrophil/lymphocyte ratio showed no overall change, and hematocrit decreased significantly. New World flying squirrels therefore appear to have a stress response that differs from many other mammals. The selective forces driving the physiology of these animals remain elusive, but this lineage may provide an interesting comparative system for the study of stress axis function and its evolution among vertebrates.

scholarly journals Interferon-beta: treatment option against COVID-19

2020 ◽  
Vol 6 (3) ◽  
Author(s):  
Faiz Ul Haq ◽  
Muhammad Usman Khan ◽  
Ayesha Muazzam ◽  
Hajrah Farooq ◽  
Javeria Iqbal ◽  
...  
Keyword(s):  
Treatment Option ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Final Analysis ◽  
Significant Activity ◽  
Interferon Β ◽  
Wholesale Market ◽  
Current Review ◽  
Novel Coronavirus ◽  
Approved Drugs

In December 2019, an increasing number of cases of novel coronavirus (2019-nCoV) that were linked to seafood wholesale market have identified in Wuhan, China. Taxonomist declared 2019-nCoV as severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) and the disease termed as COVID-19. Importantly, there is no approved drugs or vaccine against SARS-CoV-2. Current review is related to address treatment option for COVID-19. Interferon-β have shown significant activity against previous outbreak of SARS-CoV and MERS-CoV. Faced with an ongoing pandemic of SARS-CoV-2 and lack of effective treatment options, identifying compounds with antiviral activity has become a high priority. Efficacy of these treatments is still unclear. Therefore, final analysis is important to develop better treatment strategies for ongoing pandemic.

scholarly journals Structural and Functional Characterization of Host FHL1 Protein Interaction with Hypervariable Domain of Chikungunya Virus nsP3 Protein

2020 ◽  
Vol 95 (1) ◽  
Author(s):  
Tetyana Lukash ◽  
Tatiana Agback ◽  
Francisco Dominguez ◽  
Nikita Shiliaev ◽  
Chetan Meshram ◽  
...  
Keyword(s):  
Viral Replication ◽  
Binding Site ◽  
Cell Lines ◽  
Binding Sites ◽  
Chikungunya Virus ◽  
Biological Significance ◽  
Host Factors ◽  
Published Data ◽  
Wide Range ◽  
Infection Spread

ABSTRACT Decades of insufficient control have resulted in unprecedented spread of chikungunya virus (CHIKV) around the globe, and millions have suffered from the highly debilitating disease. Nevertheless, the current understanding of CHIKV-host interactions and adaptability of the virus to replication in mosquitoes and mammalian hosts is still elusive. Our new study shows that four-and-a-half LIM domain protein (FHL1) is one of the host factors that interact with the hypervariable domain (HVD) of CHIKV nsP3. Unlike G3BPs, FHL1 is not a prerequisite of CHIKV replication, and many commonly used cell lines do not express FHL1. However, its expression has a detectable stimulatory effect(s) on CHIKV replication, and Fhl1 knockout (KO) cell lines demonstrate slower infection spread. Nuclear magnetic resonance (NMR)-based studies revealed that the binding site of FHL1 in CHIKV nsP3 HVD overlaps that of another proviral host factor, CD2AP. The structural data also demonstrated that FHL1-HVD interaction is mostly determined by the LIM1 domain of FHL1. However, it does not mirror binding of the entire protein, suggesting that other LIM domains are involved. In agreement with previously published data, our biological experiments showed that interactions of CHIKV HVD with CD2AP and FHL1 have additive effects on the efficiency of CHIKV replication. This study shows that CHIKV mutants with extensive modifications of FHL1- or both FHL1- and CD2AP-binding sites remain viable and develop spreading infection in multiple cell types. Our study also demonstrated that other members of the FHL family can bind to CHIKV HVD and thus may be involved in viral replication. IMPORTANCE Replication of chikungunya virus (CHIKV) is determined by a wide range of host factors. Previously, we have demonstrated that the hypervariable domain (HVD) of CHIKV nsP3 contains linear motifs that recruit defined families of host proteins into formation of functional viral replication complexes. Now, using NMR-based structural and biological approaches, we have characterized the binding site of the cellular FHL1 protein in CHIKV HVD and defined the biological significance of this interaction. In contrast to previously described binding of G3BP to CHIKV HVD, the FHL1-HVD interaction was found to not be a prerequisite of viral replication. However, the presence of FHL1 has a stimulatory effect on CHIKV infectivity and, subsequently, the infection spread. FHL1 and CD2AP proteins were found to have overlapping binding sites in CHIKV HVD and additive proviral functions. Elimination of the FHL1-binding site in the nsP3 HVD can be used for the development of stable, attenuated vaccine candidates.

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