An Optimization-Based Method as long as the Design of Novel Molecular SystemsKyle V. Ca

An Optimization-Based Method as long as the Design of Novel Molecular SystemsKyle V. Ca

An Optimization-Based Method as long as the Design of Novel Molecular SystemsKyle V. Ca

Campbell, Dee Ann, Managing Editor has reference to this Academic Journal, PHwiki organized this Journal An Optimization-Based Method as long as the Design of Novel Molecular SystemsKyle V. Camarda Chemical in addition to Petroleum Engineering Department The University of KansasOptimization, Search in addition to Graph-Theoretical Algorithms as long as Chemical Compound SpaceIPAM, UCLAApril 15, 2011OutlineBackground: Computational Molecular DesignApplication to Ionic LiquidsExcipient Design: Including the SystemConclusions in addition to Future DirectionsMethodology: Molecular DesignPhysicalPropertyTargetsCompleteMolecularStructureTopologicalIndicescomputecorrelateOptimizationForward ProblemInverse ProblemThe as long as ward problem, determining function given a structure, may be solved experimentally, via simulation, or approximately via predictive models The inverse problem, or the product design problem, requires optimization to find a set of c in addition to idate molecules with properties close to targets chosen by the designer

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Molecular CharacterizationPhysicalPropertyTargetsCompleteMolecularStructureTopologicalIndicescomputecorrelateOptimizationIn order to quickly compute property values as long as a novel c in addition to idate ionic liquid, we need to describe key structural features with just a few easy-to-compute valuesConnectivity Indices: 0 , 1v Values based on molecular graphUniquely define 2-D topology of moleculeEncode in as long as mation about:Valence shell hybridizationInner shell electronsElectronic structure of bonded atom pairsQSPR GenerationPhysicalPropertyTargetsCompleteMolecularStructureTopologicalIndicescomputecorrelateOptimization In this step, we solve the as long as ward problem: the creation of a model to estimate physical, chemical or biological properties of a molecular system

Spanning the Molecular Space Experiments to measure properties of interest as long as molecules of known structure are needed to provide data with which to build correlationsConsistency is key!Selection of representative molecules is important – cost vs. coverageAs more complex systems/properties are considered, use of literature data becomes riskyQuantitative Structure-Property Relations (QSPR)Bicerano (1996, 2002) correlated noncrosslinked polymer properties with connectivity indicesKier in addition to Hall (1986) employed similar structural descriptors to predict KOW as long as various classes of drug moleculesSatyanarayana et al. (2009) applied connectivity indices to estimate missing UNIFAC groupsWe have generated new correlations based on topological indices which predict physical in addition to chemical properties within ~10%Descriptor Selection (from the R statistical package)

Example Predictive Model IL + R-134a(all correlations based on 19 ionic liquid systems)Methodology: Molecular DesignPhysicalPropertyTargetsCompleteMolecularStructureTopologicalIndicescomputecorrelateOptimizationThe predictive model is embedded in an optimization framework to find the molecular structure which results in properties most closely matching the targets Problem FormulationObjective functionProperty prediction modelStructural feasibility constraints For a complex property prediction model, a large nonconvex MINLP usually results

Structural Constraints While connectivity index-based CMD gives a complete molecular structure, constraints are needed to ensure that the structure is reasonableValencyConnectednessAvoidance of obviously unstable groupsRing strain estimationSolution MethodologiesComplete enumeration: The QSPR model is only valid as long as combinations of those functional groups found in the molecules experimentally tested. If this makes the solution space small enough, then complete enumeration may be used.MILP or MINLP: if the possible set of molecules is too large as long as enumeration, st in addition to ard optimization approaches may be usedStochastic optimization: if nonconvex or highly complex models in addition to constraints are used (like a neural network model), stochastic methods can still give us good solutionsTabu Search A stochastic optimization method that has been used to solve scheduling problems in addition to constraint satisfaction problems TS is a meta-heuristic approach that guides a local search procedure to explore the solution space beyond local optima. TS per as long as ms a “guided search” by taking advantage of a memory consisting of historical in as long as mation of the search process. Helps to ensure that all regions of the search space are investigatedMinimizes the likelihood of becoming stuck in a local optimum.

Product Design Software An easy-to-use graphical tool as long as drawing in addition to computing structural descriptors of ionic liquid systems Includes a database as long as building property correlations, in addition to inputs/outputs to many st in addition to ard molecular file as long as mats Includes subgraph isomorphism algorithm from Ullmann (1976) as long as determining similarity of structures, Tabu search as long as designing novel structuresSoftware Package as long as Descriptor CalculationsSoftware Package as long as Descriptor Calculations

Ionic Liquids Project: Motivation Ionic liquids (IL’s) are attracting significant industrial in addition to academic interest due to a set of unique properties: Immeasurable vapor pressure, thus non-flammable in addition to non-volatile Ability to solvate both polar in addition to nonpolar compounds Tunable properties based on anion/cation selection Computational Molecular Design (CMD) provides a method to guide the development of novel IL’s as long as specific applicationsApplications IL’s are currently being evaluated as long as use in systems such as Refrigerants (st in addition to -alone or as mixture components) Solvents as long as extraction (Zhao et al. 2005) Reaction media in addition to heat transfer fluids (Brennecke in addition to Maginn, 2001) Thus a product selection/design scheme is needed to choose the best IL as long as a given applicationExample: 1-butyl-3-methylimidazolium hexafluorophosphate

Need as long as Molecular Design As many as 1014 anion/cation combinations may give feasible IL properties The guess- in addition to -test approach is there as long as e of questionable utility Eike et al. (2004) have shown that prediction of activity coefficients of ionic liquids by correlation with structural descriptors can be effectiveTarget Properties: Ionic liquidsA number of physical in addition to chemical properties need target values or ranges when designing a novel IL-mixed refrigerant:Solubility DiffusivityViscosityMelting pointThermal Decomposition TemperatureToxicityNote that some of these targets may conflict, in the sense that replacing a given functional group may bring one property value closer to its target, but bring another one farther from its target Example Predictive Model IL + R-134a(all correlations based on 19 ionic liquid systems)

Campbell, Dee Ann Choctaw Sun Managing Editor

Example: Novel IL Refrigerant To test the design as long as mulation in addition to the software, example IL’s were designed as long as use in a refrigeration cycle, in a mixture with R-134aThree target property values were set: Groups to be selected in c in addition to idate anions are all represented in the set of IL’s used in the correlations, such that the QSPR model is validOptimal Structure The problem was as long as mulated as an MILP in addition to solved via GAMS/CPLEX in about 3 minutesStabilizing Polymers as long as Protein DrugsPeptide in addition to protein drugs are known to be unstable in many cases, even in the lyophilized state. A recent case of a protein drug which aggregated prior to injection lead to fatalities during a clinical trialExperimental results from Topp (2006) have found that the polymer poly(vinylpyrrolidone) significantly inhibited certain peptides from undergoing degradation This goal of this project is to design novel excipients, polymeric or otherwise, which inhibit specific degradation pathways. The models must include in as long as mation about the excipient in addition to the protein, so that an excipient can be tailored to the specific pharmaceutical product

The First QuestionCan we predict the most prevalent route of degradation as long as a specific protein or peptide from numerical descriptors of structureMinimized structures on PDBSimulations on peptidesExperimental dataWe need a larger-scale model as long as prediction than GC or connectivity indices can give usAlso, the 3-D structure is criticalProtein DescriptorsGiven that we have the folded structure of the protein from the PDB, what do we know about the protein as a wholeNumber of amino acids & disulfide bonds% alpha-helical, % beta-sheet, % ionicSurface characteristics:% Polar surface area% Hydrophobic surface areaWhich ones might be good predictors of aggregation or deamidation

Future Directions For larger molecular systems, three-dimensional descriptors are needed, which require an estimated minimized structure. The Tabu search algorithm has not yet been tuned as long as maximum per as long as mance, nor have we yet taken advantage of its inherent parallelizability Current work on biomolecule design seeks to “close the loop”: actually synthesize a few promising c in addition to idates, measure their properties, update the QSPR models, in addition to redesign as neededAcknowledgements Ionic Liquids: Brock Roughton, John Eslick, Prof. Aaron Scurto, Nicholas Hoffmann, John White Excipients: Brock Roughton, S in addition to ipan Sinha, Steele Reynolds, Anthony Pokphanh, Prof. Elizabeth ToppOthers: Dr. Bao Lin, Dr. Dave Miller, Prof. Rafiqul Gani + CAPECFunding Sources: Kimberly-Clark Corporation, KU Honors Program, NIH R01 DE14392

Campbell, Dee Ann Managing Editor

Campbell, Dee Ann is from United States and they belong to Choctaw Sun and they are from  Gilbertown, United States got related to this Particular Journal. and Campbell, Dee Ann deal with the subjects like Features/Lifestyle; Local News; Regional Interest

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