scholarly journals Newly designed analogues from SARS-CoV inhibitors mimicking the druggable properties against SARS-CoV-2 and its novel variants

2021 ◽  
Author(s):  
Nadim Ferdous ◽  
Mahjerin Nasrin Reza ◽  
Md. Shariful Islam ◽  
Md. Tabassum Hossain Emon ◽  
Mohamed A. Nassan ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Md Simulations ◽  
New Drugs ◽  
Antiviral Compounds ◽  
Main Protease ◽  
Novel Variants ◽  
Poisson Boltzmann ◽  
The Stability

Abstract The emerging variants of SARS Coronavirus-2 (SARS-CoV-2) has been continuously spreading all over the world and raised global health concerns. The B.1.1.7 (United Kingdom), P.1 (Brazil), B.1.351 (South Africa) and B.1.617 (India) variants resulted due to multiple mutations in the spike glycoprotein (SGp), are resistant to neutralizing antibodies and enable increased transmission. Hence, new drugs might be of great importance against the novel variants of SARS-CoV-2. The SGp and main protease (Mpro) of SARS-CoV-2 are important targets to design and develop antiviral compounds for new drug discovery. In this study, we selected seventeen phytochemicals and later performed molecular docking to determine the binding interactions of the compounds with the two receptors and calculated several drug likeliness properties for each compound. Luteolin, myricetin and quercetin demonstrated higher affinity for both the proteins and interacted efficiently. To get better compounds, we designed three analogues from these compounds and showed the greater druggable properties than the parent compounds. Furthermore, we found that the analogues bind to the residues of both proteins including the recent novel variants of SARS-CoV-2. The binding study was further verified by molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) approaches by assessing the stability of the complexes. MD simulations revealed that Arg457 of SGp and Met49 of Mpro are the most important residues that interacted with the designed inhibitors. Our analysis may give some breakthroughs to develop new therapeutics to treat the proliferation of SARS-CoV-2 in vitro and in vivo.

scholarly journals In-Silico Evaluation of Tiryaq-E-Wabai, an Unani Formulation for its Potency against SARS-CoV-2 Spike Glycoprotein and Main Protease

2021 ◽  
Vol 11 (4-S) ◽  
pp. 86-100
Author(s):  
N ZAHEER AHMED ◽  
DICKY JOHN DAVIS ◽  
NOMAN ANWAR ◽  
ASIM ALI KHAN ◽  
RAM PRATAP MEENA ◽  
...  
Keyword(s):  
In Silico ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Spike Glycoprotein ◽  
Unani Medicine ◽  
Main Protease ◽  
Pubchem Database ◽  
The Stability

COVID-19 was originated in Wuhan, China, in December 2019 and has been declared a pandemic disease by WHO. The number of infected cases continues unabated and so far, no specific drug approved for targeted therapy. Hence, there is a need for drug discovery from traditional medicine. Tiryaq-e-Wabai is a well-documented formulation in Unani medicine for its wide use as prophylaxis during epidemics of cholera, plague and other earlier epidemic diseases. The objective of the current study is to generate in-silico evidence and evaluate the potency of Tiryaq-e-Wabai against SARS-CoV-2 spike (S) glycoprotein and main protease (3CLpro). The structures of all phytocompounds used in this study were retrieved from PubChem database and some were built using Marvin Sketch. The protein structure of the SARS-CoV-2 S glycoprotein and 3CLpro was retrieved from the PDB ID: 6LZG and 7BQY respectively. AutoDock Vina was used to predict top ranking poses with best scores. The results of the molecular docking showed that phytocompounds of Tiryaq-e-Wabai exhibited good docking power with spike glycoprotein and 3CLpro. Among tested compounds Crocin from Zafran and Aloin A from Sibr showed strong binding to spike glycoprotein and 3CLpro respectively. Molecular dynamics simulation confirmed the stability of the S glycoprotein-Crocin and 3CLpro-Aloin A complexes. The Unani formulation Tiryaq-e-Wabai has great potential to inhibit the SARS-CoV-2, which have to be substantiated with further in-vitro and in-vivo studies. Keywords: In-silico study, SARS-CoV-2, Tiryaq-e-Wabai, Unani formulation, Crocin, Aloin A

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals Computational and In Vitro Experimental Investigations Reveal Anti-Viral Activity of Licorice and Glycyrrhizin against Severe Acute Respiratory Syndrome Coronavirus 2

2021 ◽  
Vol 14 (12) ◽  
pp. 1216
Author(s):  
Ahmed M. Tolah ◽  
Lamya M. Altayeb ◽  
Thamir A. Alandijany ◽  
Vivek Dhar Dwivedi ◽  
Sherif A. El-Kafrawy ◽  
...  
Keyword(s):  
Simulation Analysis ◽  
Experimental Investigations ◽  
Treatment Protocols ◽  
Infection Treatment ◽  
Main Protease ◽  
Reference Ligand ◽  
Pre Treatment ◽  
The Stability

Without effective antivirals, the COVID-19 pandemic will likely continue to substantially affect public health. Medicinal plants and phytochemicals are attractive therapeutic options, particularly those targeting viral proteins essential for replication cycle. Herein, a total 179 phytochemicals of licorice (Glycyrrhiza glabra) were screened and scrutinized against the SARS-CoV-2 main protease (Mpro) with considerable binding affinities in the range of −9.831 to −2.710 kcal/mol. The top 10 compounds with the best docking scores, licuraside, glucoliquiritin apioside, 7,3′-Dihydroxy-5′-methoxyisoflavone, licuroside, kanzonol R, neoisoliquiritin, licochalcone-A, formononetin, isomucronulatol, and licoricone, were redocked using AutoDock Vina, yielding −8.7 to −7.3 kcal/mol binding energy against Glycyrrhizin (−8.0 kcal/mol) as a reference ligand. Four compounds, licuraside, glucoliquiritin apioside, 7,3′-Dihydroxy-5′-methoxyisoflavone, and licuroside, with glycyrrhizin (reference ligand) were considered for the 100 ns MD simulation and post-simulation analysis which support the stability of docked bioactive compounds with viral protein. In vitro studies demonstrated robust anti-SARS-CoV-2 activity of licorice and glycyrrhizin under different treatment protocols (simulations treatment with viral infection, post-infection treatment, and pre-treatment), suggesting multiple mechanisms for action. Although both compounds inhibited SARS-CoV-2 replication, the half-maximal inhibitory concentration (IC50) of glycyrrhizin was substantially lower than licorice. This study supports proceeding with in vivo experimentation and clinical trials and highlights licorice and glycyrrhizin as potential therapeutics for COVID-19.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

Formation and Structure of Casein Micelles in Lactating Mammary Tissue

1970 ◽  
Vol 28 ◽  
pp. 150-151
Author(s):  
Robert J. Carroll ◽  
Marvin P. Thompson ◽  
Harold M. Farrell
Keyword(s):  
Size Distribution ◽  
G Protein ◽  
Milk Proteins ◽  
Mammary Tissue ◽  
Colloidal System ◽  
Casein Micelles ◽  
The Stability

Milk is an unusually stable colloidal system; the stability of this system is due primarily to the formation of micelles by the major milk proteins, the caseins. Numerous models for the structure of casein micelles have been proposed; these models have been formulated on the basis of in vitro studies. Synthetic casein micelles (i.e., those formed by mixing the purified αsl- and k-caseins with Ca2+ in appropriate ratios) are dissimilar to those from freshly-drawn milks in (i) size distribution, (ii) ratio of Ca/P, and (iii) solvation (g. water/g. protein). Evidently, in vivo organization of the caseins into the micellar form occurs in-a manner which is not identical to the in vitro mode of formation.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

Applicability of Instability Index for In vitro Protein Stability Prediction

2019 ◽  
Vol 26 (5) ◽  
pp. 339-347 ◽  
Author(s):  
Dilani G. Gamage ◽  
Ajith Gunaratne ◽  
Gopal R. Periyannan ◽  
Timothy G. Russell
Keyword(s):  
Protein Stability ◽  
Caulobacter Crescentus ◽  
Effect Of Temperature ◽  
Instability Index ◽  
Dipeptide Composition ◽  
Experimental Conditions ◽  
The Stability ◽  
Vitro Protein

Background: The dipeptide composition-based Instability Index (II) is one of the protein primary structure-dependent methods available for in vivo protein stability predictions. As per this method, proteins with II value below 40 are stable proteins. Intracellular protein stability principles guided the original development of the II method. However, the use of the II method for in vitro protein stability predictions raises questions about the validity of applying the II method under experimental conditions that are different from the in vivo setting. Objective: The aim of this study is to experimentally test the validity of the use of II as an in vitro protein stability predictor. Methods: A representative protein CCM (CCM - Caulobacter crescentus metalloprotein) that rapidly degrades under in vitro conditions was used to probe the dipeptide sequence-dependent degradation properties of CCM by generating CCM mutants to represent stable and unstable II values. A comparative degradation analysis was carried out under in vitro conditions using wildtype CCM, CCM mutants and two other candidate proteins: metallo-β-lactamase L1 and α -S1- casein representing stable, borderline stable/unstable, and unstable proteins as per the II predictions. The effect of temperature and a protein stabilizing agent on CCM degradation was also tested. Results: Data support the dipeptide composition-dependent protein stability/instability in wt-CCM and mutants as predicted by the II method under in vitro conditions. However, the II failed to accurately represent the stability of other tested proteins. Data indicate the influence of protein environmental factors on the autoproteolysis of proteins. Conclusion: Broader application of the II method for the prediction of protein stability under in vitro conditions is questionable as the stability of the protein may be dependent not only on the intrinsic nature of the protein but also on the conditions of the protein milieu.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

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