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Szczęście i ciężka praca w opracowywaniu leków

Koroniak Łukasz

Wiadomości Chemiczne

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2020

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[Z] 74, 3-4

135--144

EN

Luck is one of the critical factors determining outcome of many activities we are involved in. In chemistry, and specifically in drug discovery a strike of luck can determine a successful study outcome leading to an approval of potentially blockbuster drug consequently offering a new treatment option for patients in need. On the other hand, lack of luck can often result in termination of activities, wasted resources and years of studies and often have negative impact on a fate of companies and its employees. In a similar fashion, hard work is critical for one’s success. It is not meant in a literal fashion, but rather from the perspective of “going the extra mile” in scientific research and development. It is meant as a proper approach to analysis of study outcome and understanding the reasons “why”, rather than accepting simply yes/no outcomes. Below article discusses two instances where certain level of luck and extra effort invested in understanding of widely available results led to development of two novel therapeutics in oncology field. Described stories deal with development of Abraxane, novel formulation of paclitaxel commercialized by Abraxis Bioscience as well as enzalutamid (Xtandi®) discovered at UCLA and developed and commercialized by Medivation and Astellas Pharma.

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Soft computing tools for virtual drug discovery

Hagan D., Hagan M.

Journal of Artificial Intelligence and Soft Computing Research

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2018

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Vol. 8, No. 3

173--189

EN

In this paper, we describe how several soft computing tools can be used to assist in high throughput screening of potential drug candidates. Individual small molecules (ligands) are assessed for their potential to bind to specific proteins (receptors). Committees of multilayer networks are used to classify protein-ligand complexes as good binders or bad binders, based on selected chemical descriptors. The novel aspects of this paper include the use of statistical analyses on the weights of single layer networks to select the appropriate descriptors, the use of Monte Carlo cross-validation to provide confidence measures of network performance (and also to identify problems in the data), the addition of new chemical descriptors to improve network accuracy, and the use of Self Organizing Maps to analyze the performance of the trained network and identify anomalies. We demonstrate the procedures on a large practical data set, and use them to discover a promising characteristic of the data. We also perform virtual screenings with the trained networks on a number of benchmark sets and analyze the results.

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Dializa równowagowa. Metoda badania selektywności oddziaływań ligand.DNA

Czerwińska I., Głuszyńska A., Juskowiak B.

Wiadomości Chemiczne

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2010

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[Z] 64, 1-2

105-122

EN

Equilibrium or competition dialysis is a powerful tool for binding study of ligands that are expected to bind to nucleic acids with selectivity related to their structure or sequence. In the equilibrium dialysis experiment, a set of nucleic acid samples that differ in structure and sequence is dialyzed against a test ligand solution. After equilibration, the concentration of ligand bound to each structure or sequence is determined by UV-Vis absorption or fluorescence spectroscopy in each dialysis unit. Since all nucleic acid samples are in equilibrium with the same free ligand concentration, the amount of bound ligand is directly related to the ligand binding affinity. Thus, equilibrium provides a direct measure of selectivity and identifies the nucleic acid sample, which is preferred by a particular ligand. We describe here the principles and practice of the method. Examples of an application of the method are limited to the discovery of small molecules that selectively recognize the unique structural features of G-quadruplexes. There are proofs for important functional roles of G-quadruplex structures in biology (maintenance of telomeres, transcriptional regulation, and modulation of mRNA translation). G-quadruplex DNA can exist in a variety of structural forms that may possess numerous potential binding sites for small molecules. Therefore equilibrium dialysis provides a useful tool for discovery of new mall-molecule therapeutic agents targeting G-quadruplexes.