Method development drug discovery phase

Computational methods are essential in processing the vast data streams from sequencing efforts, shuctural information, protein analysis and differential gene expression. Computational approaches serve to integrate the research, development and discovery phases. An example of such efforts is the study of drug-likeness with respect to ADME parameters, in particular BBB penetration. ... 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

During the early stages of drug discovery, a suitable candidate must be selected from a limited number of structurally related compounds that may have a similar pharmacological profile. At that point, information from in vitro systems would provide important and particularly useful selection criteria. However, results from in vitro models are often not yet available at the early phases of development, or they exist only for a limited number of compounds. Accordingly, there is an urgent need for in silico methods that would allow prediction of the pharmacological properties in humans from the experimental model systems. 

ESI has become the most commonly used interface for LC/MS. It was recognized by John Fenn and co-workers as an important interface for LC/MS immediately after they developed it as an ionization technique for MS. ESI transforms ions in solution to ions in the gas phase and may be used to analyze any polar molecule that makes a preformed ion in solution. The technique has facilitated the ionization of heat-labile compounds and high-molecular-weight molecules such as proteins and peptides. ESI is a continuous ionization method that is particularly suitable for use as an interface with FiPLC. It is the most widely accepted soft-ionization technique for the determination of molecular weights of a wide variety of analytes and, has made a significant impact on drug discovery and development since the late 1980s. 

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