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1.
Pharmaceuticals (Basel) ; 14(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800393

RESUMO

eTRANSAFE is a research project funded within the Innovative Medicines Initiative (IMI), which aims at developing integrated databases and computational tools (the eTRANSAFE ToxHub) that support the translational safety assessment of new drugs by using legacy data provided by the pharmaceutical companies that participate in the project. The project objectives include the development of databases containing preclinical and clinical data, computational systems for translational analysis including tools for data query, analysis and visualization, as well as computational models to explain and predict drug safety events.

2.
Pharmaceuticals (Basel) ; 14(4)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919737

RESUMO

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new 'direct' InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL-1). These compounds offer good opportunities as leads for further optimisation.

3.
Int J Toxicol ; 40(3): 285-298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33525949

RESUMO

A workshop entitled "Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis" was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

4.
ALTEX ; 38(2): 187-197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33637997

RESUMO

Pre-competitive data sharing can offer the pharmaceutical industry significant benefits in terms of reducing the time and costs involved in getting a new drug to market through more informed testing strategies and knowledge gained by pooling data. If sufficient data is shared and can be co-analyzed, then it can also offer the potential for reduced animal usage and improvements in the in silico prediction of toxicological effects. Data sharing benefits can be further enhanced by applying the FAIR Guiding Principles, reducing time spent curating, transforming and aggregating datasets and allowing more time for data mining and analysis. We hope to facilitate data sharing by other organizations and initiatives by describing lessons learned as part of the Enhancing TRANslational SAFEty Assessment through Integrative Knowledge Management (eTRANSAFE) project, an Innovative Medicines Initiative (IMI) partnership which aims to integrate publicly available data sources with proprietary preclinical and clinical data donated by pharmaceutical organizations. Methods to foster trust and overcome non-technical barriers to data sharing such as legal and IPR (intellectual property rights) are described, including the security requirements that pharmaceutical organizations generally expect to be met. We share the consensus achieved among pharmaceutical partners on decision criteria to be included in internal clearance pro­cedures used to decide if data can be shared. We also report on the consensus achieved on specific data fields to be excluded from sharing for sensitive preclinical safety and pharmacology data that could otherwise not be shared.


Assuntos
Mineração de Dados , Disseminação de Informação , Animais , Simulação por Computador , Indústria Farmacêutica
5.
Mutagenesis ; 34(1): 111-121, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30281100

RESUMO

As part of the hazard and risk assessment of chemicals in man, it is important to assess the ability of a chemical to induce mutations in vivo. Because of the commonalities in the molecular initiating event, mutagenicity in vitro can correlate well to the in vivo endpoint for certain compound classes; however, the difficulty lies in identifying when this correlation holds true. In silico alerts for in vitro mutagenicity may therefore be used as the basis for alerts for mutagenicity in vivo where an expert assessment is carried out to establish the relevance of the correlation. Taking this into account, a data set of publicly available transgenic rodent gene mutation assay data, provided by the National Institute of Health Sciences of Japan, was processed in the expert system Derek Nexus against the in vitro mutagenicity endpoint. The resulting predictivity was expertly reviewed to assess the validity of the observed correlations in activity and mechanism of action between the two endpoints to identify suitable in vitro alerts for extension to the in vivo endpoint. In total, 20 alerts were extended to predict in vivo mutagenicity, which has significantly improved the coverage of this endpoint in Derek Nexus against the data set provided. Updating the Derek Nexus knowledge base in this way led to an increase in sensitivity for this data set against this endpoint from 9% to 66% while maintaining a good specificity of 89%.


Assuntos
Simulação por Computador , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/química , Animais , Humanos , Mutagênicos/toxicidade , Projetos de Pesquisa , Sensibilidade e Especificidade
7.
Mutagenesis ; 31(1): 17-25, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26142242

RESUMO

While the in vivo genotoxicity of a compound may not always correlate well with its activity in in vitro test systems, for certain compound classes a good overlap may exist between the two endpoints. The difficulty, however, lies in establishing the cases where this relationship holds true and selecting the most appropriate protocol to highlight any potential in vivo hazard. With this in mind, a project was initiated in which existing structural alerts for in vitro chromosome damage in the expert system Derek Nexus were assessed for their relevance to in vivo activity by assessing their predictivity against an in vivo chromosome damage data set. An expert assessment was then made of selected alerts. Information regarding the findings from specific in vivo tests was added to the alert along with any significant correlations between activity and test protocol or mechanism. A total of 32 in vitro alerts were updated using this method resulting in a significant improvement in the coverage of in vivo chromosome damage in Derek Nexus against a data set compiled by the mammalian mutagenicity study group of Japan. The detailed information relating to in vivo activity and protocol added to the alerts in combination with the mechanistic information provided will prove useful in directing the further testing of compounds of interest.


Assuntos
Aberrações Cromossômicas , Simulação por Computador , Dano ao DNA , Mutagênicos/toxicidade , Software , Animais , Cromossomos/efeitos dos fármacos , Humanos , Mamíferos/genética , Testes de Mutagenicidade
8.
Nat Protoc ; 5(12): 1967-73, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21127494

RESUMO

A concise and highly efficient synthetic route to L-azidohomoalanine (L-Aha) and its homologues is presented here. These chemically modified amino acids are used for the introduction of bioorthogonal handles into proteins. The described route avoids major problems of previously reported methods including expensive starting materials, low efficiency, and lack of scalability. Starting from inexpensive N-Boc-O-Bn-L-aspartic acid, gram quantities of L-Aha hydrochloride can be prepared with high purity. The reactions can be completed within 1 week and the products can be incorporated into proteins using L-methionine auxotrophs.


Assuntos
Alanina/análogos & derivados , Alanina/síntese química , Alanina/química , Alanina/metabolismo , Ácido Aspártico/química , Estrutura Molecular , Proteínas/metabolismo
9.
J Med Chem ; 51(24): 7751-67, 2008 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19053833

RESUMO

The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such urea-based ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using short-term cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.


Assuntos
Quadruplex G , Ureia/química , Motivos de Aminoácidos , Linhagem Celular Tumoral , Dicroísmo Circular , DNA/química , Transferência Ressonante de Energia de Fluorescência , Humanos , Substâncias Intercalantes/farmacologia , Cinética , Ligantes , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Termodinâmica
10.
Chem Commun (Camb) ; (42): 5295-7, 2008 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-18985188

RESUMO

A series of diarylurea ligands were designed to interact selectively with G-quadruplexes and were synthesised using copper(I) catalysed 'click' chemistry to incorporate the 1,4-substituted 1,2,3-triazole ring into the core of the ligands; the optimal ligands demonstrate a high degree of selective telomeric G-quadruplex stabilisation and are not cytotoxic in several cancer cell lines.


Assuntos
Quadruplex G , Triazóis/química , Ureia/análogos & derivados , Ureia/química , Animais , Sítios de Ligação , Catálise , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre/química , DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transferência Ressonante de Energia de Fluorescência , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular
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