Hit and lead generation: beyond high-throughput screening

Bleicher, Konrad H.; Böhm, Hans‐Joachim; Müller, Klaus; Alanine, Alexander

doi:10.1038/nrd1086

Cited by 970 publications

(673 citation statements)

References 41 publications

Supporting

Mentioning

644

Contrasting

Unclassified

Order By: Relevance

“…1 The need is increasingly pressing because previously containable pathogenic organisms such as Mycobacterium tuberculosis, the seventh leading cause of death worldwide, 2 Clostridium difficiles, and Streptococcus aureus continue to develop multidrug resistance. At the same time, new targets are being identified through genome sequencing and proteomics at an increasing pace.…”

Section: Introductionmentioning

confidence: 99%

Protein denaturation and protein:drugs interactions from intrinsic protein fluorescence measurements at the nanolitre scale

et al. 2010

View full text Add to dashboard Cite

Protein stability and ligand-binding affinity measurements are widely required for the formulation of biopharmaceutical proteins, protein engineering and drug screening within life science research. Current techniques either consume too much of often precious biological or compound materials, in large sample volumes, or alternatively require chemical labeling with fluorescent tags to achieve measurements at submicrolitre volumes with less sample. Here we present a quantitative and accurate method for the determination of protein stability and the affinity for small molecules, at only 1.5-20 nL optical sample volumes without the need for fluorescent labeling, and that takes advantage of the intrinsic tryptophan fluorescence of most proteins. Coupled to appropriate microfluidic sample preparation methods, the sample requirements could thus be reduced 85,000-fold to just 10 8 molecules. The stability of wild-type FKBP-12 and a destabilizing binding-pocket mutant are studied in the presence and absence of rapamycin, to demonstrate the potential of the technique to both drug screening and protein engineering. The results show that 75% of the interaction energy between FKBP-12 and rapamycin originates from residue Phe99 in the binding site.

show abstract

Section: Introductionmentioning

confidence: 99%

Protein denaturation and protein:drugs interactions from intrinsic protein fluorescence measurements at the nanolitre scale

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Drug discovery is typically a long and very expensive process, requiring an average of 10 to 20 years and an investment of more than $1.0 billion before a new compound with activity against a specifi c target is identifi ed, characterized, and developed for clinical applications (25) (26) . In the case of leishmaniasis, there are few new antileishmanial drugs in the pipeline, and drug resistance is increasing.…”

Section: Amphotericin B and Its Delivery Systems For The Treatment Ofmentioning

confidence: 99%

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

Chávez-Fumagalli

Ribeiro

Castilho

et al. 2015

Rev. Soc. Bras. Med. Trop.

View full text Add to dashboard Cite

Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit rati

show abstract

“…The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery [1][2][3]. Advances in medicinal chemistry at the interface of chemistry and biology have created an important foundation in the search for new drug candidates possessing a combination of optimized pharmacodynamic and pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Fragment-based QSAR: perspectives in drug design

Salum

Andricopulo

2009

Mol Divers

View full text Add to dashboard Cite

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure-activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.

show abstract

Hit and lead generation: beyond high-throughput screening

Cited by 970 publications

References 41 publications

Protein denaturation and protein:drugs interactions from intrinsic protein fluorescence measurements at the nanolitre scale

Protein denaturation and protein:drugs interactions from intrinsic protein fluorescence measurements at the nanolitre scale

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

Fragment-based QSAR: perspectives in drug design

Contact Info

Product

Resources

About