In silico prospection of antineoplastic molecules from the Artemisia annua species

Lung cancer kills the most men and the second that kills the most women (behind only breast cancer). The in silico study makes it possible to search for new drugs at low cost, with a greater possibility of rapid manufacturing and a lower future cost for their manufacture. The objective of this study was to analyze an antineoplastic activity of the compounds of Artemisia annua to obtain an active substance that can reach the molecular target of the cancer cells. Compounds with antineoplastic effects were selected using Scielo, PubMed, and ScienceDirect platforms. Afterward, the first screening of compound compounds was performed with a high ability to predict biological and pharmacological activity through the PASS Prediction, Pubchem, and Swiss ADME platforms. After the current screening, we determined the toxicological and molecular target prediction by the Portox II and Swiss Target Prediction platforms. As a final part, molecular docking and redocking were performed for a compound using the PDB server and the GOLD Suite 5.7.0 program. For another, we completed the pharmacophoric mapping using the Binding DB and PharmaGist database. The compounds scopoletin and caffeic acid were the most promising structures in silico models capable of interacting with EGFR (epidermal growth factor) and MM-9 (metalloproteinase type 9), respectively. The results obtained that these structures are promising to be tested in in vitro and in vivo tests about the antineoplastic activity. In addition, in silico analyses help to understand the biological effects of A. annua extracts regarding antineoplastic evidence.

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In Silico Study of Potential Cross-Kingdom Plant MicroRNA Based Regulation in Chronic Myeloid Leukemia

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692118666200106113610 ◽

2020 ◽

Vol 17 (2) ◽

pp. 125-132

Author(s):

Marjanu Hikmah Elias ◽

Noraziah Nordin ◽

Nazefah Abdul Hamid

Keyword(s):

Targeted Therapy ◽

In Silico ◽

Structure Prediction ◽

Tertiary Structure ◽

Target Prediction ◽

In Silico Analysis ◽

Microrna Target ◽

Good Target

Background: Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML. Objective: This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1. Methods: In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively. Results: In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility. Conclusion: It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.

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Chagas Disease Drug Discovery

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114550585 ◽

2014 ◽

Vol 20 (1) ◽

pp. 22-35 ◽

Cited By ~ 152

Author(s):

Eric Chatelain

Keyword(s):

Chagas Disease ◽

New Technologies ◽

Low Cost ◽

Screening Strategy ◽

New Drugs ◽

In Vivo Models ◽

The Right ◽

The Impact

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed.

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Human Tissue in the Evaluation of Safety and Efficacy of New Medicines: A Viable Alternative to Animal Models?

ISRN Pharmaceutics ◽

10.5402/2011/806789 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Robert A. Coleman

Keyword(s):

In Silico ◽

High Sensitivity ◽

Test Methods ◽

Biological Data ◽

Human Cells ◽

New Drugs ◽

Safety And Efficacy ◽

Potential Safety

The pharma Industry's ability to develop safe and effective new drugs to market is in serious decline. Arguably, a major contributor to this is the Industry's extensive reliance on nonhuman biology-based test methods to determine potential safety and efficacy, objective analysis of which reveals poor predictive value. An obvious alternative approach is to use human-based tests, but only if they are available, practical, and effective. While in vivo (phase 0 microdosing with high sensitivity mass spectroscopy) and in silico (using established human biological data), technologies are increasingly being used, in vitro human approaches are more rarely employed. However, not only are increasingly sophisticated in vitro test methods now available or under development, but the basic ethically approved infrastructure through which human cells and tissues may be acquired is established. Along with clinical microdosing and in silico approaches, more effective access to and use of human cells and tissues in vitro provide exciting and potentially more effective opportunities for the assessment of safety and efficacy of new medicines.

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Plasmodium Falciparum Infection: In Silico Preliminary Studies

Abakós ◽

10.5752/p.2316-9451.2016v5n1p63 ◽

2016 ◽

Vol 5 (1) ◽

pp. 63

Author(s):

Andréia Patricia Gomes ◽

Brenda Silveira Valles Moreira ◽

Felipe José Dutra Dias ◽

Victor Hiroshi Bastos Inoue ◽

Gabriel Vita Silva Franco ◽

...

Keyword(s):

Plasmodium Falciparum ◽

In Silico ◽

Ethical Issues ◽

Plasmodium Knowlesi ◽

Low Cost ◽

Plasmodium Malariae ◽

Infection Process ◽

Host Cells

<div class="page" title="Page 3"><div class="layoutArea"><div class="column">Malaria is an infectious disease of great impact in terms of public health, given the number of people affected and subjected to the risk of illness. Protozoa of the genus Plasmodium cause it and five species can infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi; the first is able to produce the most severe cases of the disease. Despite its clinical and epidemiological relevance and investigations in development – targeted at different aspects of the interaction between humans and Plasmodium protozoa of the genus – there remains many questions about different aspects of the malaria pathophysiology. To study such gaps, interdisciplinary strategies can be pursed, which involve biology, medicine an computer science, as part of the trial in silico. Such approach provides agility, low cost and does not imply ethical issues that permeate the experiments in vitro and in vivo. Based on these considerations, this article presents preliminary results of a computational model of the interaction between P. falciparum and erythrocytes, implemented in AutoSimmune system. The results obtained show that the system is able to simulate the host cells infection process by protozoan with similarities with the biological reality. </div></div></div>

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Organs-on-a-chip

Toxicology Research and Application ◽

10.1177/2397847317726351 ◽

2017 ◽

Vol 1 ◽

pp. 239784731772635 ◽

Cited By ~ 8

Author(s):

David Bovard ◽

Anita Iskandar ◽

Karsta Luettich ◽

Julia Hoeng ◽

Manuel C Peitsch

Keyword(s):

Biological Effects ◽

Three Dimensional ◽

In Vitro Models ◽

New Drugs ◽

New Paradigm ◽

Mechanisms Of Toxicity ◽

Culture Models ◽

Dose Responses

In the last few years, considerable attention has been given to in vitro models in an attempt to reduce the use of animals and to decrease the rate of preclinical failure associated with the development of new drugs. Simple two-dimensional cultures grown in a dish are now frequently replaced by organotypic cultures with three-dimensional (3-D) architecture, which enables interactions between cells, promoting their differentiation and increasing their in vivo likeness. Microengineering now enables the incorporation of small devices into 3-D culture models to reproduce the complex microenvironment of the modeled organ, often referred to as organs-on-a-chip (OoCs). This review describes various OoCs developed to mimic liver, brain, kidney, and lung tissues. Current challenges encountered in attempts to recreate the in vivo environment are described, as well as some examples of OoCs. Finally, attention is given to the ongoing evolution of OoCs with the aim of solving one of the major limitations in that they can only represent a single organ. Multi-organ-on-a-chip (MOC) systems mimic organ interactions observed in the human body and aim to provide the features of compound uptake, metabolism, and excretion, while simultaneously allowing for insights into biological effects. MOCs might therefore represent a new paradigm in drug development, providing a better understanding of dose responses and mechanisms of toxicity, enabling the detection of drug resistance and supporting the evaluation of pharmacokinetic–pharmacodynamics parameters.

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In Silico Driven Prediction of MAPK14 Off-Targets Reveals Unrelated Proteins with High Accuracy

10.1101/2020.07.24.219071 ◽

2020 ◽

Author(s):

Florian Kaiser ◽

Maximilian G. Plach ◽

Christoph Leberecht ◽

Thomas Schubert ◽

V. Joachim Haupt

Keyword(s):

Side Effects ◽

In Silico ◽

Target Identification ◽

Low Cost ◽

Time Frame ◽

New Drugs ◽

Drug Candidate ◽

Delivery Times ◽

Target Screening

During the discovery and development of new drugs, candidates with undesired and potentially harmful side-effects can arise at all stages, which poses significant scientific and economic risks. Most of such phenotypic side-effects can be attributed to binding of the drug candidate to unintended proteins, so-called off-targets. The early identification of potential off-targets is therefore of utmost importance to mitigate any downstream risks. We showcase how the combination of knowledge-based in silico off-target screening and state-of-the-art biophysics can be applied to rapidly identify off-targets for a MAPK14 inhibitor. Out of 13 predicted off-targets, six proteins were confirmed to interact with the inhibitor in vitro, which translates to an exceptional hit rate of 46%. For two proteins, affinities in the lower micromolar range were obtained: The kinase IRE1 and the Hematopoietic Prostaglandin D Synthase, which is entirely unrelated to MAPK14 and is involved in different cell-regulatory processes. The whole off-target identification/validation pipeline can be completed as fast as within two months, excluding delivery times of proteins. These results emphasize how computational off-target screening in combination with MicroScale Thermophoresis can effectively reduce downstream development risks in a very competitive time frame and at low cost.

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Biological Effects of Propolis on Cancer

Turkish Journal of Agriculture - Food Science and Technology ◽

10.24925/turjaf.v8i3.573-579.2939 ◽

2020 ◽

Vol 8 (3) ◽

pp. 573

Author(s):

Hamide Doğan ◽

Sibel Silici ◽

Ahmet Ata Ozcimen

Keyword(s):

Biological Activity ◽

Side Effects ◽

Biological Effects ◽

Chemotherapeutic Agents ◽

New Drugs ◽

In Vivo Studies ◽

Pharmacological Properties ◽

Bee Colony

Propolis is a special resin and wax material collected from the leaves and shells of trees, buds and shoots of plants by honey bees (Apis mellifera L.). In recent years, many researchers have studied the chemical composition, biological activity and pharmacological properties of propolis. The colour, odour and pharmacological properties of the propolis composition also vary as the composition changes depending on the plant, region, season and bee colony. Flavonoids, aromatic acids, phenolic acids and esters are the main compounds responsible for the biological activity of propolis. A number of studies have been conducted on the use of propolis or its active ingredients in the treatment of cancer. It has been observed that the use of propolis did not cause side effects according to in-vitro and in-vivo studies. Propolis should be extracted with different compounds for use in biological assays. The most commonly used compounds for extraction are ethanol, methanol, oil and water. A number of studies have been carried out showing the antitumor effect of propolis in cell culture and animal tests. The search for new drugs derived from natural products, which may function as chemotherapeutic agents and have low side effects, has increased in recent years. Combination with antioxidant therapy may improve the side effects of chemotherapy on leukocytes, liver and kidney, thus increasing the effect of chemotherapy with dose increase.

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Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings

Frontiers in Neurology ◽

10.3389/fneur.2021.725566 ◽

2021 ◽

Vol 12 ◽

Author(s):

Allison B. Coffin ◽

Robert Boney ◽

Jordan Hill ◽

Cong Tian ◽

Peter S. Steyger

Keyword(s):

Hearing Loss ◽

Drug Development ◽

In Silico ◽

Structural Similarity ◽

New Drugs ◽

Drug Induced ◽

Clinical Drug Development ◽

Clinical Drug

Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of in silico screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at in silico, in vitro, and in vivo levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.

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Selection of safe artemisinin derivatives using a machine learning-based cardiotoxicity platform and in vitro and in vivo validation

Archives of Toxicology ◽

10.1007/s00204-021-03058-4 ◽

2021 ◽

Author(s):

Onat Kadioglu ◽

Sabine M. Klauck ◽

Edmond Fleischer ◽

Letian Shan ◽

Thomas Efferth

Keyword(s):

Machine Learning ◽

In Silico ◽

Artemisia Annua ◽

Reproductive Toxicity ◽

Toxicity Prediction ◽

Artemisinin Derivatives ◽

Drug Candidates

AbstractThe majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of utmost importance, to increase the efficiency of the drug discovery process. For this purpose, we developed a toxicity prediction platform with machine-learning strategies. Cardiotoxicity prediction was performed by establishing a model with five parameters (arrhythmia, cardiac failure, heart block, hypertension, myocardial infarction) and additional toxicity predictions such as hepatotoxicity, reproductive toxicity, mutagenicity, and tumorigenicity are performed by using Data Warrior and Pro-Tox-II software. As a case study, we selected artemisinin derivatives to evaluate the platform and to provide a list of safe artemisinin derivatives. Artemisinin from Artemisia annua was described first as an anti-malarial compound and later its anticancer properties were discovered. Here, random forest feature selection algorithm was used for the establishment of cardiotoxicity models. High AUC scores above 0.830 were achieved for all five cardiotoxicity indications. Using a chemical library of 374 artemisinin derivatives as a case study, 7 compounds (deoxydihydro-artemisinin, 3-hydroxy-deoxy-dihydroartemisinin, 3-desoxy-dihydroartemisinin, dihydroartemisinin-furano acetate-d3, deoxyartemisinin, artemisinin G, artemisinin B) passed the toxicity filtering process for hepatotoxicity, mutagenicity, tumorigenicity, and reproductive toxicity in addition to cardiotoxicity. Experimental validation with the cardiomyocyte cell line AC16 supported the findings from the in silico cardiotoxicity model predictions. Transcriptomic profiling of AC16 cells upon artemisinin B treatment revealed a similar gene expression profile as that of the control compound, dexrazoxane. In vivo experiments with a Zebrafish model further substantiated the in silico and in vitro data, as only slight cardiotoxicity in picomolar range was observed. In conclusion, our machine-learning approach combined with in vitro and in vivo experimentation represents a suitable method to predict cardiotoxicity of drug candidates.

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Current Strategies in Assessment of Nanotoxicity: Alternatives to In Vivo Animal Testing

International Journal of Molecular Sciences ◽

10.3390/ijms22084216 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4216

Author(s):

Hung-Jin Huang ◽

Yu-Hsuan Lee ◽

Yung-Ho Hsu ◽

Chia-Te Liao ◽

Yuh-Feng Lin ◽

...

Keyword(s):

In Silico ◽

Biological Effects ◽

Animal Experiments ◽

Quantitative Structure Activity Relationship ◽

Alternative Methods ◽

Animal Testing ◽

Qsar Modeling ◽

Experimental Animals

Millions of experimental animals are widely used in the assessment of toxicological or biological effects of manufactured nanomaterials in medical technology. However, the animal consciousness has increased and become an issue for debate in recent years. Currently, the principle of the 3Rs (i.e., reduction, refinement, and replacement) is applied to ensure the more ethical application of humane animal research. In order to avoid unethical procedures, the strategy of alternatives to animal testing has been employed to overcome the drawbacks of animal experiments. This article provides current alternative strategies to replace or reduce the use of experimental animals in the assessment of nanotoxicity. The currently available alternative methods include in vitro and in silico approaches, which can be used as cost-effective approaches to meet the principle of the 3Rs. These methods are regarded as non-animal approaches and have been implemented in many countries for scientific purposes. The in vitro experiments related to nanotoxicity assays involve cell culture testing and tissue engineering, while the in silico methods refer to prediction using molecular docking, molecular dynamics simulations, and quantitative structure–activity relationship (QSAR) modeling. The commonly used novel cell-based methods and computational approaches have the potential to help minimize the use of experimental animals for nanomaterial toxicity assessments.

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