Advances in In-Silico based Predictive In-Vivo Profiling of Novel Potent β-Glucuronidase Inhibitors

2019 ◽  
Vol 19 (11) ◽  
pp. 906-918
Author(s):  
Maria Yousuf
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Medicinal Chemistry ◽  
Rational Drug Design ◽  
Colorectal Carcinogenesis ◽  
Human Pharmacokinetics ◽  
Design And Development ◽  
Permeability Characteristics

Background: Intestinal β-glucuronidase enzyme has a significant importance in colorectal carcinogenesis. Specific inhibition of the enzyme helps prevent immune reactivation of the glucuronide- carcinogens, thus protecting the intestine from ROS (Reactive Oxidative Species) mediatedcarcinogenesis. Objective: Advancement in In-silico based techniques has provided a broad range of studies to carry out the drug design and development process smoothly using SwissADME and BOILED-Egg tools. Methods: In our designed case study, we used SwissADME and BOILED-Egg predictive computational tools to estimate the physicochemical, human pharmacokinetics, drug-likeness, medicinal chemistry properties and membrane permeability characteristics of our recently In-vitro evaluated novel β-Glucuronidase inhibitors. Results: Out of the eleven screened potent inhibitors, compound (8) exhibited excellent bioavailability radar against the six molecular descriptors, good (ADME) Absorption, Distribution, Metabolism and Excretion along with P-glycoprotein, CYP450 isozymes and membranes permeability profile. On the basis of these factual observations, it is to be predicted that compound (8) can achieve in-vivo experimental clearance efficiently, Therefore, in the future, it can be a drug in the market to treat various disorders associated with the overexpression of β-Glucuronidase enzyme such as various types of cancer, particularly hormone-dependent cancer such as (breast, prostate, and colon cancer). Moreover, other compounds (1-7, & 9-11), have also shown good predictive pharmacokinetics, medicinal chemistry, BBB and HIA membranes permeability profiles with slight lead optimization to obtain improved results. Conclusion: In consequence, in-silico based studies are considered to provide robustness for a rational drug design and development approach to avoid the possibility of failures of drug candidates in the later stages of drug development phases. The results of this study effectively reveal the possible attributes of potent β-Glucuronidase inhibitors, for further experimental evaluation.

From serendipity to rational drug design in brain disorders: in silico, in vitro, and in vivo approaches

2021 ◽  
Vol 60 ◽  
pp. 177-182
Author(s):  
Hyunjung Oh ◽  
Thomas D. Prevot ◽  
Dwight Newton ◽  
Etienne Sibille
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Rational Drug Design ◽  
Brain Disorders ◽  
Rational Drug

Enzyme regulation by biological disulfides

1989 ◽  
Vol 9 (5) ◽  
pp. 593-604 ◽  
Author(s):  
Raul N. Ondarza
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Regulatory Mechanism ◽  
Enzyme Regulation ◽  
Rational Drug Design ◽  
Host Cells ◽  
Disulfide Exchange ◽  
Rational Drug

More than a dozen enzymes have been found to be activated or inhibited in vitro by disulfide-exchange between the protein and small-molecule disulfides. Accordingly, thiol/disulfide ratio changes in vivo may be of great importance in the regulation of cellular metabolism. An awareness of this regulatory mechanism in both host cells and parasites, coupled with information on the presence or absence of key enzymes, may lead to rational drug design against certain diseases involving thiol intermediates, including trypanosomiasis.

scholarly journals Rational Drug Design of Targeted and Enzyme Cleavable Vitamin E Analogs as Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of Cardiotoxicity of Doxorubicin.

2021 ◽  
Author(s):  
Raghu S Pandurangi ◽  
Orsolya Cseh ◽  
Artee Luchman ◽  
siguang Xu ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Vitamin E ◽  
Drug Design ◽  
Cancer Cells ◽  
Water Solubility ◽  
Therapeutic Index ◽  
Rational Drug Design ◽  
In Vivo Evaluation ◽  
Rational Drug

Traditional drug design focus on specific target (s) expressed by cancer cells. However, cancer cells outsmart the interventions by activating survival pathways and/or downregulating cell death pathways. As the research in molecular biology of cancer grows exponentially, new methods of drug designs are needed to target multiple pathways/targets which are involved in survival of cancer cells. Vitamin E analogues including a-tocopheryl succinate (TOS) is a well-known anti-tumoregenic agent which is well studied both in vitro and in vivo tumor models. However, lack of targeting cancer cells and unexpected toxicity along with the poor water solubility of TOS compelled a rational drug design using both targeting and cleavable technologies incorporated in the new drug design. A plethora of Vitamin E derivatives (AMP-001, 002 and 003) were synthesized, characterized and studied for the improved efficacy and lowered toxicity in various cancer cells in vitro. Preliminary studies revealed AAAPT leading candidates reduced the invasive potential of brain tumor stem cells, synergized with different drugs and different treatments. AAAPT leading drug AMP-001 enhanced the therapeutic index of front-line drug Doxorubicin in triple negative breast cancer (TNBC) tumor rat model preserving the ventricular function when used as a neoadjuvant to Doxorubicin. These results may pave the way for reducing the cardiotoxicity of chemotherapy in clinical settings.

scholarly journals A Relational Learning Approach to Structure-Activity Relationships in Drug Design Toxicity Studies

2011 ◽  
Vol 8 (3) ◽  
pp. 176-194 ◽  
Author(s):  
Rui Camacho ◽  
Max Pereira ◽  
Vítor Santos Costa ◽  
Nuno A. Fonseca ◽  
Carlos Adriano ◽  
...  
Keyword(s):  
Drug Design ◽  
Medicinal Chemistry ◽  
Software Tool ◽  
Rational Drug Design ◽  
Learning System ◽  
Toxic Effects ◽  
Graphical Interface ◽  
Data Set ◽  
Structure Activity

Summary It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current “target-rich, lead-poor” scenario.Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal - iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms.

Part-II- in silico drug design: application and success

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shaheen Begum ◽  
Mohammad Zubair Shareef ◽  
Koganti Bharathi
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Hiv Protease ◽  
Pharmacokinetic Parameters ◽  
Hiv Protease Inhibitors ◽  
Animal Testing ◽  
Ligand Complex ◽  
Structure Based Drug Design

Abstract In silico tools have indeed reframed the steps involved in traditional drug discovery and development process and the term in silico has become a familiar term in pharmaceutical sector like the terms in vitro and in vivo. The successful design of HIV protease inhibitors, Saquinavir, Indinavir and other important medicinal agents, initiated interest of researchers in structure based drug design approaches (SBDD). The interactions between biomolecules and a ligand, binding energy, free energy and stability of biomolecule-ligand complex can be envisioned and predicted by applying molecular docking studies. Protein-ligand, protein-protein, DNA-ligand interactions etc. aid in elucidating molecular level mechanisms of drug molecules. In the Ligand based drug design (LBDD) approaches, QSAR studies have tremendously contributed to the development of antimicrobial, anticancer, antimalarial agents. In the recent years, multiQSAR (mt-QSAR) approaches have been successfully employed for designing drugs against multifactorial diseases. Output of a research in several instances is rewarding when both SBDD and LBDD approaches are combined. Application of in silico studies for prediction of pharmacokinetics was once a real challenge but one can see unlimited number publications comprising tools, data bases which can accurately predict almost all the pharmacokinetic parameters. Absorption, distribution, metabolism, transporters, blood brain barrier permeability, hERG toxicity, P-gp affinity and several toxicological end points can be accurately predicted for a candidate molecule before its synthesis. In silico approaches are greatly encouraged a result of growing limitations and new legislations related to the animal use for research. The combined use of in vitro data and in silico tools will definitely decrease the use of animal testing in the future.In this chapter, in silico approaches and their applications are reviewed and discussed giving suitable examples.

Emerging Need of Today: Significant Utilization of Various Databases and Softwares in Drug Design and Development

2020 ◽  
Vol 20 ◽  
Author(s):  
Neema Bisht ◽  
Archana N. Sah ◽  
Sandeep Bisht ◽  
Himanshu Joshi
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Interdisciplinary Studies ◽  
Design And Development ◽  
Target Interaction ◽  
Pharmacokinetic Properties ◽  
In Vivo Testing ◽  
Speed Up ◽  
Experimental Use

: In drug discovery, in silico methods have become a very important part of the process. These approaches impact the entire development process by discovering and identifying new target proteins as well as designing potential ligands with a significant reduction of time and cost. Furthermore, in silico approaches are also preferred because of reduction in experimental use of animals as; in vivo testing, for safer drug design and repositioning of known drugs. Novel software based discovery and development such as direct/indirect drug design, molecular modelling, docking, screening, drugreceptor interaction, and molecular simulation studies are very important tools for the predictions of ligand-target interaction pattern, pharmacodynamics as well as pharmacokinetic properties of ligands. On the other part, the computational approaches can be numerous, requiring interdisciplinary studies and the application of advance computer technology to design effective and commercially feasible drugs. This review mainly focuses on the various databases and softwares used in drug design and development for speed up the process.

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

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.

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

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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