In Silico, In Vitro and In Vivo Analysis of Binding Affinity between N and C-Domains of Clostridium perfringens Alpha Toxin

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

Download Full-text

Gestational influences on the pharmacokinetics of gestagenic drugs: A combined in silico, in vitro and in vivo analysis

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2010.12.003 ◽

2011 ◽

Vol 42 (4) ◽

pp. 318-331 ◽

Cited By ~ 9

Author(s):

Sabine Pilari ◽

Cornelia Preuße ◽

Wilhelm Huisinga

Keyword(s):

In Silico ◽

In Vivo Analysis

Download Full-text

Investigation of biological activities of Colocasia gigantea Hook.f. leaves and PASS prediction, in silico molecular docking with ADME/T analysis of its isolated bioactive compounds

10.1101/2020.05.18.101113 ◽

2020 ◽

Author(s):

Safaet Alam ◽

Nazim Uddin Emon ◽

Mohammad A. Rashid ◽

Mohammad Arman ◽

Mohammad Rashedul Haque

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Castor Oil ◽

Biological Activities ◽

Kappa Opioid Receptor ◽

Soluble Extract ◽

Docking Score

AbstractBackgroundColocasia gigantea is locally named as kochu and also better known due to its various healing power. This research is to investigate the antidiarrheal, antimicrobial, and antioxidant possibilities of the methanol soluble extract of Colocasia gigantea.MethodsAntidiarrheal investigation was performed by using in vivo castor oil induced diarrheal method where as in vitro antimicrobial and antioxidant investigation have been implemented by disc diffusion and DPPH scavenging method respectively. Moreover, in silico studies were followed by molecular docking analysis of several secondary metabolites were appraised with Schrödinger-Maestro v 11.1.ResultsThe induction of plant extract (200 and 400 mg/kg, b.w, p.o), the castor oil mediated diarrhea has been minimized 19.05 % (p < 0.05) and 42.86 % (p < 0.001) respectively. The methanolic extract of C. gigantea showed mild sensitivity against almost all the tested strains but it shows high consistency of phenolic content and furthermore yielded 67.68 μg/mL of IC50 value in the DPPH test. The higher and lower binding affinity was shown in beta-amyrin and monoglyceryl stearic acid against the kappa-opioid receptor (PDB ID: 4DJH) with a docking score of -3.28 kcal/mol and -6.64 kcal/mol respectively. In the antimicrobial investigation, Penduletin and Beta-Amyrin showed the highest and lowest binding affinity against the selected receptors with the docking score of -8.27 kcal/mol and -1.66 kcal/mol respectively.ConclusionThe results of our scientific research reflect that the methanol soluble extract of C. gigantea is safe which may provide possibilities of alleviation of diarrhea and as a potential wellspring of antioxidants which can be considered as an alternate source for exploration of new medicinal products.

Download Full-text

Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An in Silico Study

Medicinal Chemistry ◽

10.2174/1573406417666210208223924 ◽

2021 ◽

Vol 17 ◽

Author(s):

Mojgan Nejabat ◽

Razieh Ghodsi ◽

Farzin Hadizadeh

Keyword(s):

Binding Affinity ◽

In Silico ◽

Oral Absorption ◽

Antiviral Agent ◽

In Vivo Studies ◽

Reference Drug ◽

Viral Proteases ◽

In Silico Study

Background: The Covid-19 virus emerged a few months ago in China and infections rapidly escalated into a pandemic. Objective: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. Method: In this work two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. Result: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets – S2, TMPRSS2 and furin – simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. Conclusion: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

Download Full-text

In silico and in vivo analysis of binding affinity of estrogens with estrogen receptor alpha in Channa punctatus (Bloch)

Fish Physiology and Biochemistry ◽

10.1007/s10695-014-0003-z ◽

2014 ◽

Vol 41 (1) ◽

pp. 31-40 ◽

Cited By ~ 5

Author(s):

S. Pipil ◽

V. Kumar ◽

V. S. Rawat ◽

L. Sharma ◽

N. Sehgal

Keyword(s):

Estrogen Receptor ◽

Binding Affinity ◽

In Silico ◽

Estrogen Receptor Alpha ◽

Channa Punctatus ◽

Receptor Alpha ◽

In Vivo Analysis

Download Full-text

In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors

Molecules ◽

10.3390/molecules26072082 ◽

2021 ◽

Vol 26 (7) ◽

pp. 2082

Author(s):

Mahmoud A. A. Ibrahim ◽

Alaa H. M. Abdelrahman ◽

Tarik A. Mohamed ◽

Mohamed A. M. Atia ◽

Montaser A. M. Al-Hammady ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Binding Affinity ◽

Red Sea ◽

Protein Interactions ◽

In Silico ◽

Target Function ◽

Pathway Enrichment Analysis ◽

Main Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.

Download Full-text

In silico, in vitro and in vivo analysis of putative virulence factors identified in large clostridial toxin-negative, binary toxin- producing C. difficile strains

Anaerobe ◽

10.1016/j.anaerobe.2019.102083 ◽

2019 ◽

Vol 60 ◽

pp. 102083 ◽

Cited By ~ 1

Author(s):

G.O. Androga ◽

D.R. Knight ◽

M.L. Hutton ◽

S.J. Mileto ◽

M.L. James ◽

...

Keyword(s):

Virulence Factors ◽

In Silico ◽

Binary Toxin ◽

In Vivo Analysis

Download Full-text

In Silico Inhibition of BACE-1 by Selective Phytochemicals as Novel Potential Inhibitors: Molecular Docking and DFT Studies

Current Drug Discovery Technologies ◽

10.2174/1570163816666190214161825 ◽

2020 ◽

Vol 17 (3) ◽

pp. 397-411 ◽

Cited By ~ 4

Author(s):

Nadia Arif ◽

Andleeb Subhani ◽

Waqar Hussain ◽

Nouman Rasool

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

In Silico ◽

Density Functional ◽

Energy Gap ◽

Human Beings ◽

Potential Inhibitors ◽

Bace 1

Background: Alzheimer’s Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings. Objective: This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis. Methods: A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals. Results: The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1. Conclusion: Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.

Download Full-text