engleski

Experimental Methods of Structure Analysis in Drug Design

Design, development, testing and marketing of the new drug is extremely expensive, tough and competitive business. Therefore, there is understandable tendency toward more rational approaches and methods in designing drug candidates. The first rationale is understanding of molecular basis of particular disease which enables intervention in metabolism at optimal point for therapeutic effect. Once the target biomolecule is chosen, the main concern is quick design of potent and selective ligand. This is where all sorts of computational and experimental tools and methods come in play. The knowledge of 3D structure of target biomolecule, ligand and especially their complexes is of crucial role for successful design of drug candidate. The target biomolecule is usually protein, enzyme or receptor, and its structure could be predicted by homology modelling or determined on the base of NMR derived data or by X-ray crystallography. The ligand is "small" molecule whose conformation is, in most cases, estimated reasonably well by force field calculation. Structure estimation of protein-ligand complexes is goal for numerous computational tools, but exact result comes only from NMR spectroscopy or, more accurately, X-ray diffraction experiments. Traditional advantages of computational methods were high throughput (speed) and low cost. However, recent advantages in synchrotron radiation sources and crystallographic instrumentation enable data collection from protein crystal to be as short as five minutes. Such speed extended application of crystallographic and NMR methods from mainly lead optimisation phase to screening phase of drug discovery process.

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