Therapeutic Potential of Novel Mastoparan-Chitosan Nanoconstructs Against Clinical MDR Acinetobacter baumannii: In silico, in vitro and in vivo Studies

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

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Exploring the therapeutic potential of atorvastatin against Gram-positive and Gram-negative bacteria: In-silico, In-vitro and In- vivo evidence

Infectious Disorders - Drug Targets ◽

10.2174/1871526519666191024162730 ◽

2019 ◽

Vol 19 ◽

Author(s):

Kamal Sethi ◽

Arti Singh ◽

Anoop Kumar

Keyword(s):

Mtt Assay ◽

In Silico ◽

Bacterial Infections ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Bacterial Strains ◽

Study Results ◽

Reference Ligand

The incidences of opportunistic bacterial infections have increased from the past two decades or threaten to increase in the near future. Inspite of the availability of various classes of antibiotics, bacterial infections are not handled properly.Thus, in the present study, we have repurposed atorvastatin against various types of bacterial strains by using in-silico, in-vitro, and in-vivo studies. Further, preliminary safety study was conducted using MTT assay. In-silico study results have revealed that atorvastatin hasgood interaction with various targets of bacterial cell as that of reference ligand. However, under in-vitro conditions, we have foundthat atorvastatin was effective at higher concentration(>128 μg/ml) against various bacterial strains. Thus, further, atorvastatin was tested in combination with standard antibiotics and has shown synergistic effect. The MTT assay results have revealed non-cytotoxic activity of atorvastatin. In conclusion, atorvastatin in combination with standard drugs could be developed as an antibacterial agent.

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Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

Current Pharmaceutical Design ◽

10.2174/1381612826666201112143230 ◽

2020 ◽

Vol 26 ◽

Author(s):

John Chen ◽

Andrew Martin ◽

Warren H. Finlay

Keyword(s):

Drug Delivery ◽

In Silico ◽

Local Drug Delivery ◽

In Vivo Studies ◽

Intranasal Drug Delivery ◽

Nasal Sprays ◽

In Silico Studies ◽

Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

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Medicinal Plants and Bioactive Compounds for Diabetes Management: Important Advances for Drug Discovery

Current Pharmaceutical Design ◽

10.2174/1381612826666200928160357 ◽

2020 ◽

Vol 26 ◽

Author(s):

Kondeti Ramudu Shanmugam ◽

Bhasha Shanmugam ◽

Gangigunta Venkatasubbaiah ◽

Sahukari Ravi ◽

Kesireddy Sathyavelu Reddy

Keyword(s):

Herbal Medicine ◽

Medicinal Plants ◽

Bioactive Compounds ◽

Diabetes Management ◽

Therapeutic Potential ◽

Public Health Problem ◽

In Vivo Studies ◽

Major Public Health Problem

Background : Diabetes is a major public health problem in the world. It affects each and every part of the human body and also leads to organ failure. Hence, great progress made in the field of herbal medicine and diabetic research. Objectives: Our review will focus on the effect of bioactive compounds of medicinal plants which are used to treat diabetes in India and other countries. Methods: Information regarding diabetes, oxidative stress, medicinal plants and bioactive compounds were collected from different search engines like Science direct, Springer, Wiley online library, Taylor and francis, Bentham Science, Pubmed and Google scholar. Data was analyzed and summarized in the review. Results and Conclusion: Anti-diabetic drugs that are in use have many side effects on vital organs like heart, liver, kidney and brain. There is an urgent need for alternative medicine to treat diabetes and their disorders. In India and other countries herbal medicine was used to treat diabetes. Many herbal plants have antidiabetic effects. The plants like ginger, phyllanthus, curcumin, aswagandha, aloe, hibiscus and curcuma showed significant anti-hyperglycemic activities in experimental models and humans. The bioactive compounds like Allicin, azadirachtin, cajanin, curcumin, querceitin, gingerol possesses anti-diabetic, antioxidant and other pharmacological properties. This review focuses on the role of bioactive compounds of medicinal plants in prevention and management of diabetes. Conclusion: Moreover, our review suggests that bioactive compounds have the potential therapeutic potential against diabetes. However, further in vitro and in vivo studies are needed to validate these findings.

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽

10.3390/molecules26092505 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2505

Author(s):

Raheem Remtulla ◽

Sanjoy Kumar Das ◽

Leonard A. Levin

Keyword(s):

Machine Learning ◽

Neural Networks ◽

In Silico ◽

Disulfide Bonds ◽

Oral Absorption ◽

In Vivo Studies ◽

Drug Candidates ◽

In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

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In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies

Journal of Molecular Modeling ◽

10.1007/s00894-011-0994-7 ◽

2011 ◽

Vol 17 (12) ◽

pp. 3063-3073 ◽

Cited By ~ 9

Author(s):

Amit Nargotra ◽

Sujata Sharma ◽

Mohd Iqbal Alam ◽

Zabeer Ahmed ◽

Asha Bhagat ◽

...

Keyword(s):

In Silico ◽

In Vivo Studies ◽

In Silico Identification

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The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Cells ◽

10.3390/cells10113088 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3088

Author(s):

Mariana Matias ◽

Jacinta O. Pinho ◽

Maria João Penetra ◽

Gonçalo Campos ◽

Catarina Pinto Reis ◽

...

Keyword(s):

Therapeutic Potential ◽

Drug Evaluation ◽

Three Dimensional ◽

Experimental Models ◽

In Vivo Studies ◽

Murine Models ◽

In Vivo Experiments ◽

Novel Therapeutic Strategies

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

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In Silico Screening of Potential Drug with Antileishmanial Activty and Validation of their Activity by in Vitro and in Vivo Studies

Journal of Chemistry and Chemical Engineering ◽

10.17265/1934-7375/2015.06.002 ◽

2015 ◽

Vol 9 (6) ◽

Cited By ~ 1

Author(s):

Carol V. Mesa ◽

Gustavo A. Blandón ◽

Diana L. Muñoz ◽

Carlos E. Muskus ◽

Andrés F. Flórez ◽

...

Keyword(s):

In Silico ◽

In Vivo Studies ◽

Potential Drug ◽

In Silico Screening

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Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

10.26434/chemrxiv.13087715 ◽

2020 ◽

Author(s):

Kui Wu ◽

Nathan Yee ◽

Sangeetha Srinivasan ◽

Amir Mahmoodi ◽

Michael Zakharian ◽

...

Keyword(s):

Therapeutic Potential ◽

Unmet Need ◽

Sodium Hyaluronate ◽

Maximum Tolerated Dose ◽

The Body ◽

In Vivo Studies ◽

Tumor Biomarker ◽

Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

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