Digalloyl Glycoside: A Potential Inhibitor of Trypanosomal PFK from Euphorbia abyssinica J.F. Gmel

Human African trypanosomiasis is an endemic infectious disease caused by Trypanosoma brucei via the bite of tsetse-fly. Most of the drugs used for the treatment, e.g., Suramin, have shown several problems, including the high level of toxicity. Accordingly, the discovery of anti-trypanosomal drugs from natural sources has become an urgent requirement. In our previous study on the anti-trypanosomal potential of Euphorbia species, Euphorbia abyssinica displayed significant anti-trypanosomal activity. Therefore, a phytochemical investigation of the methanolic extract of E. abyssinica was carried out. Twelve compounds, including two triterpenes (1, 2); one sterol-glucoside (4); three ellagic acid derivatives (3, 9, 11); three gallic acid derivatives (5, 6, 10); and three flavonoids (7, 8, 12), were isolated. The structures of isolated compounds were determined through different spectroscopic techniques. Compound (10) was obtained for the first time from genus Euphorbia while all other compounds except compound (4), were firstly reported in E. abyssinica. Consequently, an in silico study was used to estimate the anti-trypanosomal activity of the isolated compounds. Several compounds displayed interesting activity where 1,6-di-O-galloyl-d-glucose (10) appeared as the most potent inhibitor of trypanosomal phosphofructokinase (PFK). Moreover, molecular dynamics (MD) simulations and ADMET calculations were performed for 1,6-di-O-galloyl-d-glucose. In conclusion, 1,6-di-O-galloyl-d-glucose revealed high binding free energy as well as desirable molecular dynamics and pharmacokinetic properties; therefore, it could be suggested for further in vitro and in vivo studies for trypanosomiasis.

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

10.26434/chemrxiv.12442736.v1 ◽

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>

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

10.26434/chemrxiv.12442736 ◽

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

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An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

Frontiers in Pharmacology ◽

10.3389/fphar.2021.717757 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Trina Ekawati Tallei ◽

Fatimawali ◽

Afriza Yelnetty ◽

Rinaldi Idroes ◽

Diah Kusumawaty ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Three Dimensional ◽

Md Simulations ◽

Inhibitory Effect ◽

Dynamics Simulation ◽

Novel Coronavirus

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

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Identification of Structurally Similar Phytochemicals to Quercetin with High SIRT1 Binding Affinity and Improving Diabetic Wound Healing by Using In silico Approaches

Biointerface Research in Applied Chemistry ◽

10.33263/briac126.76217632 ◽

2021 ◽

Vol 12 (6) ◽

pp. 7621-7632

Keyword(s):

Wound Healing ◽

In Silico ◽

Binding Free Energy ◽

Biological Properties ◽

In Vivo Studies ◽

Diabetic Wound ◽

Binding Modes ◽

Diabetic Wound Healing

Diabetes Mellitus is the most prevalent metabolic disorder that is increasing at an alarming rate worldwide. The unregulated glucose level leads to various types of health disorders, and one of the major diabetic complications is delayed wound healing. Due to the more side effects of synthetic drugs, there is a need to explore plants and their phytochemicals for medicinal purposes. It was found that Quercetin, a flavonoid, increases the rate of diabetic wound healing by enhancing the expression of SIRT1. This demands more insight towards Quercetin and its similar compounds, as it is hypothesized that similar compounds may have similar biological properties. Thus similarity searching was done to identify the most similar compounds of Quercetin, and then the molecular docking of the screened compounds was performed using AutoDock Vina. The unique ligands were docked into the active site of SIRT1 protein (PDB ID: 4ZZJ). The binding free energy of the interacting ligand with the protein was estimated. Six compounds were identified which possess the maximum structural similarity with Quercetin, and upon docking, it was found that gossypetin and herbacetin have similar binding modes and binding energy as that of Quercetin (-7.5 kcal/mol). Therefore, the hypothesis has been validated by in silico analysis. Our study identified two phytochemicals, Gossypetin, and Herbacetin which can prove beneficial for improving diabetic wound healing but needs to be validated further by in vitro and in vivo studies.

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The anti-malignant activity of Macrotyloma uniflorum mediated green synthesized Cu and Zn metal-ligand nano complexes

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl4.4340 ◽

2020 ◽

Vol 11 (SPL4) ◽

pp. 1573-1580

Author(s):

Savita Belwal ◽

Sujana Kariveda ◽

Saritha Ramagiri ◽

Swathi A ◽

Shubham Kute ◽

...

Keyword(s):

Metal Complexes ◽

Biologically Active ◽

In Vivo Studies ◽

Chemistry Laboratory ◽

Condensation Process ◽

Spectroscopic Techniques ◽

Macrotyloma Uniflorum ◽

Cu And Zn

The green biological route has been employed to convert macro-sized zinc and copper metal complexes into nano-sized metal complexes. These bioactive metal complexes were synthesized by template condensation process in the chemistry laboratory. The newly synthesized biologically active complexes were converted into nano range from phytochemical aqueous extract of Macrotyloma uniflorum (horse gram). Biologically converted nano complexes have been characterized by physicochemical as well as spectroscopic techniques such as UV-visible spectrophotometer and FTIR. The reduced Cu and Zn metal nanoparticles were analyzed with SEM for shape and size, which showed most of the nanoparticles, were nearly spherical with nano range size. To estimate the potentiality of newly manufactured copper and zinc nanoparticles in vitro and in in vivo studies, i.e. antifungal and antibacterial and anti-cancer activities were performed. The biogenic nanoparticles of Cu and Zn were evaluated for their activity on cancer A-549 cell lines by standard MTT assay for metabolically active mitochondria and cell viability. Further flow cytometric studies showed Cu, and Zn nano complexes had inhibition efficacy of cancer cells compared to normal cells. This study elevates that biosynthesized Cu & Zn nano complexes can be an alternative for the treatment of cancer.

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HOXB9 Promotes Laryngeal Squamous Cell Carcinoma Progression by Upregulating MMP12

10.21203/rs.3.rs-554245/v1 ◽

2021 ◽

Author(s):

Chuanhui Sun ◽

Peng Wang ◽

Yujiang Chen ◽

Qiuying Li ◽

Hua Deng ◽

...

Keyword(s):

Squamous Cell ◽

Molecular Mechanisms ◽

Gene Knockout ◽

Histological Grade ◽

Cell Cancer ◽

In Vivo Studies ◽

Migration And Invasion ◽

High Level

Abstract Background：The HOX family transcription factor HOXB9 is a crucial element in the progression of various cancers. In the previous study conducted by the investigators, a drastically higher HOXB9 expression was reported in laryngeal squamous cell cancer (LSCC), when compared to adjacent normal laryngeal squamous tissues. Furthermore, a high level of HOXB9 was closely correlated with histological grade and overall survival in LSCC patients. However, the underlying molecular mechanisms have not been fully elucidated.Results: The present study explored the molecular mechanisms of HOXB9 in LSCC progression. Furthermore, the in vitro and in vivo studies revealed that the gene knockout of HOXB9 using the CRISPR/CAS9 system inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. Mechanistic studies in LSCC cell lines and human LSCC specimens demonstrated that HOXB9 promotes LSCC progression by directly upregulating the MMP12 expression at the level of its transcription.Conclusions: Collectively, the present study is the first to demonstrate the role of HOXB9 in the regulation of LSCC progression by enhancing the upregulation of MMP12.

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The activity of LE10 peptide on biological membranes using molecular dynamics, in vitro and in vivo studies

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2013.01.050 ◽

2013 ◽

Vol 106 ◽

pp. 240-247 ◽

Cited By ~ 7

Author(s):

Egipto Antunes ◽

Nuno G. Azoia ◽

Teresa Matamá ◽

Andreia C. Gomes ◽

Artur Cavaco-Paulo

Keyword(s):

Molecular Dynamics ◽

Biological Membranes ◽

In Vivo Studies

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Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Niztro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study

Pharmaceuticals ◽

10.3390/ph15010102 ◽

2022 ◽

Vol 15 (1) ◽

pp. 102

Author(s):

Blanca Colin-Lozano ◽

Héctor Torres-Gomez ◽

Sergio Hidalgo-Figueroa ◽

Fabiola Chávez-Silva ◽

Samuel Estrada-Soto ◽

...

Keyword(s):

Molecular Dynamics ◽

Spectral Analysis ◽

In Silico ◽

In Vivo Studies ◽

In Vitro Expression ◽

Modes Of Action ◽

In Vivo Effects ◽

Orally Active

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1–4, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 1–4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.

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Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

Pharmaceuticals ◽

10.3390/ph13090209 ◽

2020 ◽

Vol 13 (9) ◽

pp. 209 ◽

Cited By ~ 2

Author(s):

Rozires P. Leão ◽

Josiane V. Cruz ◽

Glauber V. da Costa ◽

Jorddy N. Cruz ◽

Elenilze F. B. Ferreira ◽

...

Keyword(s):

Binding Affinity ◽

Md Simulation ◽

Md Simulations ◽

Cyclooxygenase 2 ◽

In Vivo Studies ◽

Chemical Structures ◽

Anti Inflammatory ◽

Cyclooxygenase 2 Inhibitors

The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

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High in vitro activity of DIS-73285, a novel antimicrobial with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa322 ◽

2020 ◽

Vol 75 (11) ◽

pp. 3244-3247

Author(s):

Susanne Jacobsson ◽

Clive Mason ◽

Nawaz Khan ◽

Paul Meo ◽

Magnus Unemo

Keyword(s):

Neisseria Gonorrhoeae ◽

Small Molecule ◽

Mechanism Of Action ◽

Vitro Activity ◽

In Vivo Studies ◽

In Vitro Activity ◽

Agar Dilution ◽

High Level

Abstract Background The rising incidence of antimicrobial resistance in Neisseria gonorrhoeae may result in untreatable gonorrhoea in certain circumstances and development of novel antimicrobials is urgently needed. Objectives To evaluate the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, DIS-73285, against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates (n = 262). Methods MICs (mg/L) of DIS-73285 were determined by agar dilution and by Etest for ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline. Results DIS-73285 was substantially more potent than any of the currently or previously used therapeutic antimicrobials, with MICs ranging from ≤0.001 to 0.004 mg/L, and the MIC50, MIC90 and modal MIC all ≤0.001 mg/L (lowest MIC tested). No correlation with the MICs of DIS-73285 and the MICs of any of the currently or previously used antimicrobials was observed. Conclusions The novel chemotype, small-molecule antimicrobial DIS-73285, demonstrated high in vitro potency against all tested N. gonorrhoeae isolates. Further in vitro and in vivo studies, evaluating efficacy, resistance emergence, pharmacokinetic/pharmacodynamic parameters, toxicity and safety, should be conducted to evaluate DIS-73285 as a therapy specifically for urogenital and extra-genital gonorrhoea.

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