Drug Design
Drugs function by binding to specific locations on target molecules and causing a certain desired change, such as disabling the target or causing a conformational change. Ideally, a drug should act very specifically and bind only to its target without interfering with other biological functions. However, it is difficult to precisely determine where and how tightly two molecules will bind. Due to limitations in computational power, current in silico approaches usually have to trade speed for accuracy; e.g. use rapid protein docking methods instead of computationally expensive free energy calculations. Folding@home's computational performance allows researchers to use both techniques, and evaluate their efficiency and reliability. Computer-assisted drug design has the potential to expedite and lower the costs of drug discovery. In 2010, Folding@home used MSMs and free energy calculations to predict the native state of the villin protein to within 1.8 Å RMSD (root mean square deviation) from the crystalline structure experimentally determined through X-ray crystallography. This accuracy has implications to future protein structure prediction approaches, including for intrinsically unstructured proteins. Scientists have used Folding@home to research drug resistance by studying vancomycin, an antibiotic of "last resort", and beta-lactamase, a protein that can break down antibiotics like penicillin.
Chemical activity occurs along a protein's active site. Traditional drug design approaches involve tightly binding to this site and blocking its activity, under the assumption that the target protein exists in a single rigid structure. However, this approach only works for approximately 15% of all proteins. Proteins contain allosteric sites which, when bound to by small molecules, can alter a protein's conformation and ultimately affect the protein's activity. These sites are attractive drug targets, but locating them is very computationally expensive. In 2012, Folding@home and MSMs were used to identify allosteric site in three medically relevant proteins: beta-lactamase, interleukin-2, and RNase H.
Approximately half of all known antibiotics interfere with the workings of a bacteria's ribosome, a large and complex biochemical machine that performs protein biosynthesis by translating messenger RNA into proteins. Macrolide antibiotics clog the ribosome's exit tunnel, preventing synthesis of essential bacterial proteins. In 2007 the Pande lab received a grant to study and design new antibiotics. In 2008 they used Folding@home to study the interior of this tunnel and how specific molecules may affect it. The full structure of the ribosome has only been recently determined, and Folding@home has also simulated ribosomal proteins, as many of their functions remain largely unknown.
Read more about this topic: Folding@home, Biomedical Research
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... A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy ... Computer-aided drug design in particular becomes much more tractable when there's a high-resolution structure of a target protein bound to a potent ligand ... This approach to drug discovery is sometimes referred to as structure-based drug design ...
... The design of new ligands is usually based on the modification of known ligands for the target proteins ...
... Another approach used to develop analogs of rimonabant was to replace central pyrazole ring by another heterocycle ... An example of this approach are 4,5-diarylimidazoles and 1,5-diarylpyrrole-3-carboxamides ...
... elaborate structural studies of proteins from several important systems as potential drug targets such as phospholipase A2, cyclooxygenase, lipoxygenase, endothelin ... He had developed the rules of peptide design with alpha, beta – dehydro - amino acids through extensive studies using syntheses, and X-ray and NMR structure ... These design rules are being exploited for making specific peptides to act as tight inhibitors of target enzymes and potent antagonists of target ...
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