scholarly journals Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Sandra Duffy ◽  
Melissa L. Sykes ◽  
Amy J. Jones ◽  
Todd B. Shelper ◽  
Moana Simpson ◽  
...  
Keyword(s):  
Biological Activity ◽  
Drug Discovery ◽  
Open Access ◽  
Open Source ◽  
Target Identification ◽  
Source Model ◽  
Biological Evaluation ◽  
Neglected Diseases ◽  
Extensive Literature

ABSTRACT Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.

scholarly journals Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

2018 ◽  
Author(s):  
Wilson Lim ◽  
Youri Melse ◽  
Mickey Konings ◽  
Hung Phat Duong ◽  
Kimberly Eadie ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Open Source ◽  
Scientific Community ◽  
Galleria Mellonella ◽  
World Health ◽  
Neglected Diseases ◽  
Starting Point ◽  
Madurella Mycetomatis

AbstractEumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungusMadurella mycetomatis.A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were activein vitro.Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for theirin vitroactivity againstM. mycetomatishyphae, rendering four further hit compounds. To assess thein vivopotency of these hit compounds, aGalleria mellonellalarvae model infected withM. mycetomatiswas used. Several of the compounds identifiedin vitrodemonstrated promising efficacyin vivoin terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of anOpen Source Mycetoma (MycetOS)approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.Author summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungusMadurella mycetomatis.Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity againstM. mycetomatisin vitro and several in vivo with ourGalleria mellonellalarvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

Scientific Authorship and E-commons

2010 ◽  
pp. 193-205
Author(s):  
Luc Schneider
Keyword(s):  
Open Access ◽  
Open Source ◽  
Scientific Knowledge ◽  
Scientific Community ◽  
Scientific Literature ◽  
Source Model ◽  
Public Domain ◽  
Scientific Publications ◽  
Scientific Authorship ◽  
The Web

This contribution tries to assess how the Web is changing the ways in which scientific knowledge is produced, distributed and evaluated, in particular how it is transforming the conventional conception of scientific authorship. After having properly introduced the notions of copyright, public domain and (e-)commons, I will critically assess James Boyle's (2003, 2008) thesis that copyright and scientific (e-) commons are antagonistic, but I will mostly agree with the related claim by Stevan Harnad (2001a,b, 2008) that copyright has become an obstacle to the accessibility of scientific works. I will even go further and argue that Open Access schemes not only solve the problem of the availability of scientific literature, but may also help to tackle the uncontrolled multiplication of scientific publications, since these publishing schemes are based on free public licenses allowing for (acknowledged) re-use of texts. However, the scientific community does not seem to be prepared yet to move towards an Open Source model of authorship, probably due to concerns related to attributing credit and responsability for the expressed hypotheses and results. Some strategies and tools that may encourage a change of academic mentality in favour of a conception of scientific authorship modelled on the Open Source paradigm are discussed.

scholarly journals Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1783 ◽  
Author(s):  
Rebeka Jójárt ◽  
Péter Traj ◽  
Édua Kovács ◽  
Ágnes Horváth ◽  
Gyula Schneider ◽  
...  
Keyword(s):  
Biological Activity ◽  
Inhibitory Action ◽  
Molecular Level ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Computational Simulations ◽  
Simultaneous Application ◽  
Methyl Group ◽  
Ic50 Values

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10β-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10β-fluoroestra-1,4-dien-3-one and 10β-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13β-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13β-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

Design, Syntheses and Biological Evaluation of 3-Arylurea-5-Fluoroindolin-2-One Derivatives

2013 ◽  
Vol 634-638 ◽  
pp. 922-925
Author(s):  
Zhao Yang ◽  
Zhi Xiang Wang ◽  
Zheng Fang ◽  
Kai Guo
Keyword(s):  
Drug Discovery ◽  
1H Nmr ◽  
Elemental Analysis ◽  
Biological Evaluation ◽  
Antitumor Activities ◽  
Mtt Method ◽  
Antitumor Bioactivity ◽  
Better Than ◽  
Fragment Based Drug Discovery

Sixteen 3-arylurea-5-fluoroindolin-2-one derivatives were designed according to the principle of fragment based drug discovery and synthesized with 5-fluoroisatin as the starting material. The obtained structures were identified by 1H NMR, MS and elemental analysis. In vitro evaluation of antitumor bioactivity was performed by MTT method. Most of synthesized compounds showed antitumor activities, especially, activities of 6a, 6h, and 6j in tumor inhibition were better than others.

scholarly journals Synthesis, characterization and in vitro biological evaluation of the Schiff base derived from Benzidine and 1,3‐Diphenyl‐1,3‐propanedione

2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Emir Horozić ◽  
Jasmin Suljagić ◽  
Darja Husejnagić ◽  
Nusreta Hasić ◽  
Amra Bratovčić
Keyword(s):  
Antioxidant Activity ◽  
Biological Activity ◽  
Schiff Base ◽  
Organic Compounds ◽  
Carbonyl Compounds ◽  
Biological Evaluation ◽  
Transitional Metals ◽  
The Subject ◽  
Shiff Bases

Schiff bases are organic compounds formed by the reaction of the primary aminewith carbonyl compounds (aldehydes or ketones). These are mainly bi- or tridentateligands capable of forming very stable complexes with transitional metals. They areused as catalysts in oxygenation, hydrolysis, electro-reduction and decompositionreactions. Many Shiff bases show significant anti-tumor, antimicrobial and antifungalactivity, which are the subject of research by many scientists in the world.In this paper Schiff base from benzidine and 1,3-diphenyl-1,3-propanedione wassynthesized. To characterize the product, FTIR spectroscopy and stereo-microscopywere used. In order to determine biological activity, antibacterial, antifungal andantioxidant activity of the product was tested.The results showed that the interaction of benzidine and 1,3-diphenylpropanedioneresults in a Schiff base showing antibacterial, antifungal and antioxidant activity.

Molecular Docking in Formulation and Development

2019 ◽  
Vol 16 (1) ◽  
pp. 30-39 ◽  
Author(s):  
Tejinder Kaur ◽  
Ashwini Madgulkar ◽  
Mangesh Bhalekar ◽  
Kalyani Asgaonkar
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Dosage Form ◽  
Development Process ◽  
Critical Role ◽  
Docking Studies ◽  
Extensive Literature ◽  
Time Saving ◽  
Drug Discovery And Development

Background: In pharmaceutical research drug discovery and development process is timeconsuming and expensive. In many cases, it produces incompetent results due to the failure of in vitro and in vivo conventional approaches. Before any new drug is placed in the market it must undergo rigorous testing to get FDA approval. Due to the several limitations imposed by the drug discovery process, in recent times in silico approaches are widely applied in this field. The purpose of this review is to highlight the current molecular docking strategies used in drug discovery and to explore various advances in the field. Methods: In this review we have compiled database after an extensive literature search on docking studies which has found its applications relevant to the field of formulation and development. The papers retrieved were further screened to appraise the quality of work. In depth strategic analysis was carried out to confirm the credibility of the findings. Results: The papers included in this review highlight the promising role of docking studies to overcome the challenges in formulation and development by emphasizing it’s applications to predict drug excipient interactions which in turn assist to increase protein stability; to determine enzyme peptide interactions which maybe further used in drug development studies; to determine the most stable drug inclusion complex; to analyze structure at molecular level that ascertain an increase in solubility, dissolution and in turn the bioavailability of the drug; to design a dosage form that amplify the drug discovery and development process. Conclusion: This review summarizes recent findings of critical role played by molecular docking in the process of drug discovery and development. The application of docking approach will assist to design a dosage form in the most cost effective and time saving manner.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel C (7) Modified Analogues of Chrysin

2020 ◽  
Vol 17 (7) ◽  
pp. 873-883
Author(s):  
Pulabala Ramesh ◽  
Vankadari Srinivasa Rao ◽  
Puchakayala Muralidhar Reddy ◽  
Katragadda Suresh Babu ◽  
Mutheneni Srinivasa Rao
Keyword(s):  
Natural Products ◽  
Biological Activity ◽  
Molecular Docking ◽  
Biological Activities ◽  
Antimicrobial Activities ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies ◽  
Fungal Strains

Background:: Most of the currently available pharmaceutical drugs are either natural products or analogues of natural products. Flavonoids are plant based natural polyphenolic compounds which exhibit a wide range of biological activities. Chrysin, a natural flavone, exhibits several biological activities like antiallergic, anti-inflammatory and anticancer. Many efforts were made to enhance the biological activity of chrysin. In continuation of our work on synthetic modifications of chrysin, amino-alcohol containing heterocyclic moiety is linked to chrysin at C (7) position to enhance its biological activity. Methods:: A series of new C (7) modified analogues of chrysin (3a-k) have been designed and synthesized in two steps. Chrysin, on reacting with epichlorohydrin in the presence of K2CO3 in DMF gave epoxide (2) which was made to react with cyclic secondary amines in the presence of LiBr to form the designed products (3a-k). All the synthesized compounds (3a-k) were well characterized by 1H NMR, 13C NMR and mass spectral data. The synthesized analogues (3a-k) were screened for their in vitro biological activities against a panel of bacterial and fungal strains. Molecular docking studies were also performed on these compounds with E. coli FabH (1HNJ) and S. cerevisiae (5EQB) enzymes, to support the observed biological activities. Results:: A series of new 2-hydroxy 3-amino chrysin derivatives (3a-k) were synthesized in two steps, starting with chrysin and their structures were characterized by spectral analysis. In vitro biological activities of these analogues against a panel of bacterial and fungal strains indicated that some of the derivatives manifested significant activities compared to standard drugs. Molecular docking and binding energy values were also correlated with experimental antimicrobial screening results. Lipinski’s “rule of five” is also obeyed by these analogues (3a-k) and exhibit drug-likeness. Conclusion:: In the present study, a series of new C (7) modified chrysin analogues (3a-k) were synthesized and tested for their in vitro antimicrobial activities. These biological studies indicated that some of the derivatives exhibited moderate to good antimicrobial activities compared to standard drugs. Molecular docking studies performed on these compounds correlated with the experimental antimicrobial activities. The results obtained in the study will be useful in establishing new drug entities to control the pathogenic epidemics.

QSAR-guided semi-synthesis and in vitro validation of antiplasmodial activity in ursolic acid derivatives

RSC Advances ◽  
2015 ◽  
Vol 5 (41) ◽  
pp. 32133-32143 ◽  
Author(s):  
Komal Kalani ◽  
Harveer Singh Cheema ◽  
Himanshu Tripathi ◽  
Feroz Khan ◽  
M. P. Daroker ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Ursolic Acid ◽  
Antimalarial Drug ◽  
Qsar Model ◽  
Biological Evaluation ◽  
Antiplasmodial Activity

As a part of antimalarial drug discovery programme, a QSAR model was developed for the prediction of antiplasmodial activity in ursolic acid derivatives, followed by semi-synthesis of virtually active derivatives and their biological evaluation.

Sign in / Sign up

Export Citation Format

Share Document