Discovery experiment

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

An alternative metric to describe 3-D properties of molecules is discussed by Ashton et al.26 In their approach, a pharmacophore fingerprint is used in conjunction with conformational searching to determine possible 3-D shapes that molecules can adopt. Tools from Tripos and CDL are available to carry out this type of analysis. However as with other methods there are limitations, the completeness of conformational searching being one. Perhaps the most important limitation of the approach is that it has a tendency to pick the most flexible molecules (that set the most pharmacophore bits). In a lead discovery experiment, following up on flexible molecules can be a long and sometimes fruitless process. 

He K et al (2008) N-in-1 dosing pharmacokinetics in drug discovery experience, theoretical and practical considerations. J Pharm Sci 97 2568-2580... 

The most efficient mechanism to obtain M is e capture after stopping p+ in a suitable noble gas. This technique was employed already in the discovery experiment of the muonium atom through its characteristic muon spin rotation in a magnetic field by V.W. Hughes and collaborators in 1960. There the atoms were formed in Ar gas [8], where efficiencies of 65(5)% are possible. In the most recent precision measurements of Avhfs and the muon magnetic moment... 

The natural product discovery experiences described here confirm that microorganisms continue to represent an abundant source of interesting signal transduction inhibitors. A variety of high-throughput screening approaches for the discovery of such compounds were used with varying results. The bacterial protein histidine kinase assay resulted in the... 

The purpose of making discovery experiments for the problem of interest is to determine the conditions, which maximize the separation between the product and the neighboring impurities as well as give a system with the maximum available surface for the product. This is done with screening studies, which evaluate the feed component s... 

As discussed in Section 7.3, the optimization in chromatography proceeds as follows. From the discovery experiments the mobile-phase composition, particle size (apparent or nominal), the thermodynamic parameters and the Knox parameters are known. From the mobile-phase composition, the feed composition (simplify to a binary mixture, one impurity and the product), the viscosity can be estimated from data in the literature. The void fraction can be measured from the retention of unretained component (Eq. (7.24)), or estimated based on vendor information. The packing density is typically known by... 

Combinatorial chemistry differs from usual Monte Carlo simulations in that several simultaneous searches of the variable space are carried out. That is, in a typical combinatorial chemistry experiment, several samples, e.g., 10,000, are synthesized and screened for figure of merit at one time. With the results of this first round, a new set of samples can be synthesized and screened. This procedure can be repeated for several rounds, although current materials discovery experiments have not systematically exploited this feature. 

Fig. 1. The grid, random, and low-discrepancy sequence approaches to designing the first library in a materials discovery experiment with three compositional variables. The random approach breaks the regular pattern of the grid search, and the low-discrepancy sequence approach avoids overlapping points that may arise in the random approach.

The space of composition and noncomposition variables to search in materials discovery experiments can be forbiddingly large. Yet, by using Monte Carlo methods, one can achieve an effective search with a limited number of experimental samples. 

Thus, a second key strategy in drug discovery is to improve the planning and interpretation of discovery experiments using pharmaceutical-profiling property data. Drug-discovery researchers of all disciplines should have access to compound property data and be aware of the potential effects on the experiments they are performing. 

Property data from pharmaceutical prohling is not exclusively for optimizing PK. It can be considered as part of the multivariate ensemble of data (e.g., MW, chirality, purity, IC50, LD50) that is available to research teams for application to any drug-discovery experiment. 

Hyseq researchers have also performed comparative sequencing, re-sequenc-ing and SNP discovery experiments on several human, bacterial, and viral (e. g., HIV) genes. Reference sequences, although not required, were used to aid in the assembly steps of these applications. It was, however, not necessary to obtain... 

Students do not know the outcome of the work before they start. In that sense, they are discovery experiments in which they do the work in order to discover the answer for the client. I hope both instructors and students will have as much fun working their way through this manual as I have had preparing it. 

Astatine can be separated from bismuth by volatilizing it, although the discovery experiments performed in 1940, of course, were much more complex than this. 

This is the way that all of the actinide elements heavier than curium were chemically identified in their discovery experiments. 

The 1S-2S transition in muonium has also been measured by laser spectroscopy. The transition is induced by a two-photon Doppler-free process and detected through the subsequent photoionization of the 2S state in the laser field. The key to success in this experiment was the production of muonium into vacuum from the surface of heated W or of Si02 powder. The discovery experiment(33) was done at the KEK facility in Japan with a pulsed muon beam and an intense pulsed laser system. A subsequent experiment(34) done with the pulsed beam at RAL and a similar pulsed laser has improved the signal substantially and has achieved a a precision of about lO" in the 1S- 2S interval, thus determining the Lamb shift in the IS state to about 1% accuracy (Fig. 22). The precision of this experiment should be greatly improved in a new experiment now underway at RAL. This experiment will provide a precise... 

The neutrino plays an essential role in the models of elemoitaiy particles and in the theory of the formation and development of the universe. The existrace of the neutrino was predicted by Pauli in 1927 but it was not proven until 1956 when Reines and Cowan detected them in experiments at the Savannah River (USA) nuclear reactor. Since neutrinos are emitted in the j3-decays following fission, nuclear reactors are the most intense neutrino sources on earth. The detector in the discovery experiments consisted of a scintillating solution containing cadmium surrounded by photomultipliers to observe the scintillations which occurred as a consequoice of the following reactions ... 

The recognition of the similarity in chemical properties between the actinide and lanthanide elements was an important contributing factor in the synthesis and isolation of the transcurium elements. Most of the chemical identification was carried out by eluting the elements from columns of cation exchange resin. The pattern of the elution behavior from the resin bed of the lanthanide elements made it possible to predict with good accuracy the expected elution position for a new actinide element (Fig. 16.7). This technique constituted the most definitive chemical evidence in the discovery experiments for the elements from atomic numbers 97 through 101. More recently these conclusions have been confirmed by spectroscopy. 

---