QM/MM Study of Cytochrome P450 BM3

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QM MM Study ofCytochrome P450 BM3Catalysis Mechanism andApplication in Drug Design P450 Super family of.
monooxygenases metabolism of carbon source organicmolecules hormones vitamin D etc detoxification of xenobiotic compounds synthesis of biologically active compounds.
Why interesting in drug designThe eve of ADME in High ThroughputAbsorption by the intestineDiffusion to the organismMetabolism by the liver.
Excretion by the kidney Toxicology One half of potential drugs fail because ofADME Tox issues Of the estimated 600 million cost of bringing.
a new drug to market more than 400 millionof that is wasted pursuing leads that turn outto be dogs P450 CYP enzymes a class of enzymesresponsible for the metabolism of more than.
50 of all known drugs Enzyme P450 BM3RH O2 2e 2H R OH H2O The function of P450 enzyme in drugmetabolism is responsible for the failure of.
a good inhibitor to become a useful drug P450 BM3 the closet bacterial analog tothe mammalian enzyme soluble threedomains BMP heme domain a FAD andFMN containing NADPH cytochrome P450.
reductase Archives of Biochemistry and Biophysics 1999 369 1 Structure heme Fe S Cys and H2O as ligandsFigure shows the porphyrin ring in the active Putative conformational change.
Electron transfer NADPH FAD FMN BMP heme Conformational changefacilitated by the hinge .
moving between a closed conformation and an open conformationFMN heme distance 18 8 Dutton s line electron transfer.
kET k0ETexp R t Productive electronwithin 14 15 Munro Andrew et al Trends inBiochemical Sciences 2002.
Catalytic cycle ofcytochrome P4506a 6b and 7 putative noexperimental structureRDS 2nd e injection.
Intermediate compound I oxyferryl porphyrin cation X ray structure and product3200 mol min 1 mol of enzyme 1 NADPH rate 37 C 50 .
1JPZ X ray 1 65 BMP conversionwith N Palmitoylgolycine D C Haines et al Biochemistry Computational modelingComputational modeling proposed thefollowing binding structure B .
Jovanovic et al JACS 2005 Solid State NMR Experiment 2D solid state NMR 15N13COSPECIFIC CP spectrum of13COLeu 15N Gly 15N Phe.
labeled cytochrome P450 BM 3 bound with NPG at 0 red and 30 C blue The L86 F87 pair exhibits apronounced shift as a function.
of temperature The L86 F87pair is in the binding pocket and in fact F87 plays a gatekeeper role in that itsbulky side chain must be.
rotated in order to allow forsubstrate binding Combined Quantum mechanics Molecularmechanics QM MM is a hybrid technique tomodel enzyme catalyzed reactions .
A small reactive part of the system is treatedquantum mechanically i e by an electronicstructure method this allows the electronicrearrangements involved in a chemical reaction namely bond breaking and making to be.
modeled The large non reactive part is describedby molecular mechanics and the two regions areable to interact The combination of the efficiency and speed of theMM force field with the versatility and range of.
applicability of the QM method allows reactions inlarge systems to be studied Docking structure and QM MMQM region of P450 BM3 Docking structure Total charge 3 Spin.
Schrodinger Inc multiplicity 4 Activation Barrier in QM MMDoublet QM MM U DFT without zero point energy correction Search for P450 in PDB www rcsb org.
Search for P450 or P450 3A4 Check the hits What domain Ligands ofX ray or NMR Resolution .
QM/MM Study of Cytochrome P450 BM3 Catalysis Mechanism and Application in Drug Design P450: Super family of monooxygenases Function: metabolism of carbon-source organic molecules: hormones, vitamin D etc. detoxification of xenobiotic compounds synthesis of biologically active compounds Why interesting in drug design The eve of ADME in High-Throughput Screening Absorption by the intestine ...

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