Protein in drug discovery

Ayrton A, Morgan P (2008) Role of transport proteins in drug discovery and development a pharmaceutical perspective. Xenobiotica 38(7-8) 676-708... 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

This chapter consists of four main sections. The first provides an overall description of the process of contemporary protein structure determination by X-ray crystallography and summarizes the current computational requirements. This is followed by a summary and examples of the use of structure-based methods in drug discovery. The third section reviews the key developments in computer hardware and computational methods that have supported the development and application of X-ray crystallography over the past forty or so years. The final section outlines the areas in which improved... 

Babine RE, Abdel-Meguid SS. Protein crystallography in drug discovery (Vol. 20 of Mannhold R, Kubinyi H, Folkers G, editors. Methods and Principles in Medicinal Chemistry). Weinheim Wiley-VCH, 2004. 

Recent developments in drug discovery and drug development spurred the need for novel analytical techniques and methods. In the last decade, the biopharmaceutical industry set the pace for this demand. The nature of the industry required that novel techniques should be simple, easily applicable, and of high resolution and sensitivity. It was also required that the techniques give information about the composition, structure, purity, and stability of drug candidates. Biopharmaceuticals represent a wide variety of chemically different compounds, including small organic molecules, nucleic acids and their derivatives, and peptides and proteins. 

So far we have discussed various techniques for computing the PMF. The other type of free energy calculation commonly performed is alchemical transformation where two different systems are compared. Such calculations have many applications such as Lennard-Jones fluid with and without dipoles for each particles, comparison of ethanol (CH3CH2OH) and ethane thiol (CH3CH2SH), replacing one amino acid by another in a protein, changing the formula for a compound in drug discovery, etc. 

Evans, D.C. et al., Drug-protein adducts An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development, Chem. Res. Toxicol., 17, 3, 2004. 

Quantitation and qualification of large molecules follow similar principles as procedures for small molecules but involve different foci and approaches. The quantitation of proteins and peptides includes relative and absolute amount evaluations. Most proteomic applications in drug discovery are concerned with relative abundances of proteins. 

A major limitation in using protein NMR spectroscopy in drug discovery has been the molecular weight limitation imposed by nuclear spin relaxation (line broadening) and increased spectral complexity associated with macromolecules larger than 35 kDa [5]. The most recent developments in NMR spectroscopy aimed at overcoming these problems will be briefly reviewed in Sect. 21.2. 

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