Fragment approach

The fragment approach has sometimes been combined with a chain growth or buildup algorithm. The chain growth algorithm is one in which the full molecule is built up one unit at a time. As each unit (monomer or functional group) is added, its conformation is searched without changing the rest of the chain. This results in a CPU time requirement that is directly proportional to the number of units and is thus much faster than some of the other algorithms.  [c.186]

The program system COBRA [118, 119] can be regarded as a rule- and data-based approach, but also applies the principles of fragment-based (or template-based) methods extensively (for a detailed description sec Chapter 11, Sections 7.1 and 7.2 in the Handbook). COBRA uses a library of predefined, optimized 3D molecular fragments which have been derived from crystal structures and foi ce-field calculations. Each fi agment contains some additional information on  [c.98]

If a fragment constant is not available from the internal data basis nor can be interpolated from related data, a calculation program has to issue a missing fragment error, which is generally a problem with such fragmental approaches. In order to tackle this problem, which could result in 10-20% calculation failures for databases containing more complex structures, the CLOGP approach was recently extended by an algorithm to estimate fragment constants from scratch [10] this is based on a test set of about 600 dependably measured fragments having only aliphatic and aromatic bonds.  [c.493]

A number of other software packages are available to predict NMR spectra. The use of large NMR spectral databases is the most popular approach it utilizes assigned chemical structures. In an advanced approach, parameters such as solvent information can be used to refine the accuracy of the prediction. A typical application works with tables of experimental chemical shifts from experimental NMR spectra. Each shift value is assigned to a specific structural fragment. The query structure is dissected into fragments that are compared with the fragments in the database. For each coincidence, the experimental chemical shift from the database is used to compose the final set of chemical shifts for the  [c.519]

Fitting a ligand from a 3D structure database into the binding site of a target protein is called docking. The iterative building of new molecules in the binding site of a receptor is illustrated in the center and on the right hand side of Figure 10.4-5. These procedures to find new leads are called de novo design. The building approach, beginning with a single fragment and proceeding through the stepwise addition of further moieties, is shown in the center. Alternatively, several small molecules are placed in the binding site of the protein and subsequently linked together (linking). To end up with high-affinity ligands from structure-based drug design, a high degree of steric and electronic complementarity of the ligand to the target protein is required. Further on, an appropriate amount of the ligands hydro-phobic surface should be buried in the complex. A certain degree of conforma-  [c.608]

PRO-SELECT [77] fragment-based, scaffold-linker approach  [c.610]

The fragment-based approach to conformational analysis relies upon two assumptions. Tl first assumption is that each fragment must be conformationally independent of the oth fragments in the molecule. The second assumption is that the conformations stored fc each fragment must cover the range of structures that are observed in fully constructe molecules. The fragment conformations can be obtained from a variety of sources tv common approaches are by analysing a structural database (see Section 9.11) or froi some other conformational search method. A third limitation is that one can obvious only analyse molecules for which there are fragments available.  [c.481]

Various theoretical methods can be used to calculate partition coefficients. The partition coefficient is an equilibrium constant and so is directly related to a free energy change. Partition coefficients can be calculated using free energy perturbation methods, as discussed in Section 11.3.2. These methods suffer from the limitations of force field parametrisation and the large amoimt of computer time that is required to perform such calculations. More widely used are fragment-based approaches, in which the partition coefficient is calculated as a sum of individual fragment contributions plus a set of correction factors. Such an approach clearly depends critically upon the definition of the fragments. The widely used CLOGP program of Hansch and Leo [Leo 1993] uses a small number of compounds to accurately define a set of fragment values. CLOGP breaks a molecule into fragments by identifying isolating carbons, which are carbon atoms that are not doubly  [c.685]

ILOGP program remains the benchmark by which other methods for calculating l-water partition coefficients tend to be judged. One of its main drawbacks is the for data for all the fragments in the molecule. Whilst the requisite data for a consider-umber of fragments are included by default, the calculation will often not be correct for tion of the molecules in a typical pharmaceutical database. Of course, if the fragment is ion to a molecular series of particular interest then it is usually straightforward to rm the experiment and add the necessary fragment value. An alternative is to use an based approach to estimating the partition coefficient. This is very similar to the lent-based method, but rather than checking for fragments the molecule is broken into the atom types present. In the simplest case, the partition coefficient is given summation of the contributions from each atom type [Ghose and Crippen 1986 et al. 1998 Wang et al. 1997 Wildman and Crippen 1999]  [c.686]

As we have seen, a common route to calculating both the partition coefficient and molar refractivity is by combining in some way the contributions from the fragments or atoms in the molecule. The fragment contributions are often determined using multiple linear regression, which will be discussed below (Section 12.12.2). Such an approach can be applied to many other properties, of which we shall mention only one other here, solubility, Klopman and colleagues were able to derive a regression model for predicting aqueous solubility based upon the presence of groups, most of which corresponded to a single atom in a specific hybridisation state but also included acid, ester and amide groups [Klopman et al. 1992]. This gave a reasonably general model that was able to predict the solubility of a test set within about 1.3 log units. A more specific model which contained more groups performed better but was of less generic applicability.  [c.687]

The knowledge-based docking approach to ligand design requires the receptor site to be surveyed to identify possible hydrogen-bonding donor and acceptor sites and regions where other groups might favourably be positioned. The results of such an analysis are often converted into a distribution of site paints. A site point is a location within the binding site where an appropriate ligand atom or group could be placed. For example, a hydrogenbonding analysis would typically result in a series of donor and acceptor site points. When generating the site points one should take account of any preferred geometries for that particular type of interaction. There is usually more than one site point associated with each donor or acceptor atom in the receptor to reflect the fact that a distribution of geometries is found in the crystal structure analyses. The range of preferred geometries can also be represented as a continuous region. Having surveyed the binding site, each molecular fragment is examined to determine which features it contains, and the fragment is positioned in the site by fitting the appropriate atoms to their corresponding site points.  [c.705]

ADF uses a STO basis set along with STO fit functions to improve the efficiency of calculating multicenter integrals. It uses a fragment orbital approach. This is, in essence, a set of localized orbitals that have been symmetry-adapted. This approach is designed to make it possible to analyze molecular properties in terms of functional groups. Frozen core calculations can also be performed.  [c.333]

The N-to-C assembly of the peptide chain is unfavorable for the chemical synthesis of peptides on solid supports. This strategy can be dismissed already for the single reason that repeated activation of the carboxyl ends on the growing peptide chain would lead to a much higher percentage of racemization. Several other more practical disadvantages also tend to disfavor this approach, and acid activation on the polymer support is usually only used in one-step fragment condensations (p. 241).  [c.235]

Micronutrients in Granular Fertilizers. In the production of granular fertilizers, it is relatively simple and effective to incorporate micronutrient materials as feeds in the granulation process. A problem with this method, however, is that granulation processes are most efficient and economical when operated continuously to produce large tonnages of the same or similar composition. Frequent changes in product composition or storage of a wide range of grades is simply uneconomical. These factors seriously limit the practice of prescription micronutrient formulation in granular fertilizer production processes. Granulation processes more often use the shotgun approach. As a result, some unneeded elements are provided with no benefit.  [c.242]

These methodologies have been reviewed (22). In both methods, synthesis involves assembly of protected peptide chains, deprotection, purification, and characterization. However, the soHd-phase method, pioneered by Merrifield, dominates the field of peptide chemistry (23). In SPPS, the C-terminal amino acid of the desired peptide is attached to a polymeric soHd support. The addition of amino acids (qv) requires a number of relatively simple steps that are easily automated. Therefore, SPPS contains a number of advantages compared to the solution approach, including fewer solubiUty problems, use of less specialized chemistry, potential for automation, and requirement of relatively less skilled operators (22). Additionally, intermediates are not isolated and purified, and therefore the steps can be carried out more rapidly. Moreover, the SPPS method has been shown to proceed without racemization, whereas in fragment synthesis there is always a potential for racemization. Solution synthesis provides peptides of relatively higher purity however, the addition of hplc methodologies allows for pure peptide products from SPPS as well.  [c.200]

The lower section of a column with downward flow must have a distributor system that not only collects Hquid evenly over the cross-sectional area, but also supports the resin bed and prevents resin from leaving the column. The traditional method has been to place a network of pipes with small holes drilled in them (a distributor) in a bed of graded gravel, sand, or anthracite coal, which supports the resin bed. While that practice continues, the trend has been toward other approaches. In one modification, the underbed is eliminated by securely wrapping the pipe elements with small mesh, noncorrosive screening. The size of the screen openings must be sufficiently smaller than the resin particles to avoid plugging. Blockage of the openings increases pressure drop and contributes to uneven or channeled flow. Special pipes formed by spirally winding triangular wire around supports, while carefully controlling the space between the flat side of the wire as it is wound, is another approach that is gaining acceptance. Perforated plates separating the resin from the distributor are used in other installations. Careful design of the distributor is essential, especially for the larger diameter units (see Fluid mechanics). If the linear flow rate near the wall of the column is substantially less than the midsection of the column, premature breakthrough, more frequent regeneration, and incomplete utilization of the rated operating capacity for the resin result.  [c.381]

Development-induced adjacency effects frequentiy enhance edge contrast, which translates into desirable sharp and crisp photographs. Such chemical sharpness often compensates for the sharpness losses produced by light-scattering during exposure (34). The apparent sharpness of developed images is also influenced by certain gelatin-developer interactions, eg, the oxidized form of the developer pyrogaHol [87-66-1] (1,2,3-trihydroxybenzene) acts like a hardening or tanning agent and shrinks the gelatin. Therefore, in regions of high exposure a considerable concentration of oxidized developer is generated and a corresponding differential shrinkage of gelatin occurs upon drying. The use of tanning developers may offer yet another approach to visual sharpness control.  [c.456]

The most common approach for imparting water solubiHty to an alkyd resin is to provide free pendent carboxyl groups in the resin and neutralize them with a fugitive base, such as ammonia or low molecular weight amines, to build ionic characteristics into the resin. Nonfugitive base materials, such as caustic soda, leave the salt in the coating film and damage its water and corrosion resistance. TrimelHtic anhydride (TMA) is the most frequent ingredient chosen to provide the pendent carboxyl groups.  [c.43]

Constraint control strategies can be classified as steady-state or dynamic. In the steady-state approach, the process dynamics are assumed to be much faster than the frequency with which the constraint control appHcation makes its control adjustments. The variables characterizing the proximity to the constraints, called the constraint variables, are usually monitored on a more frequent basis than actual control actions are made. A steady-state constraint appHcation increases (or decreases) a manipulated variable by a fixed amount, the value of which is determined to be safe based on an analysis of the proximity to relevant constraints. Once the appHcation has taken the control action toward or away from the constraint, it waits for the effect of the control action to work through the lower control levels and the process before taking another control step. Usually these steady-state constraint controls are implemented to move away from the active constraint at a faster rate than they do toward the constraint. The main advantage of the steady-state approach is that it is predictable and relatively straightforward to implement. Its major drawback is that, because it does not account for the dynamics of the constraint and manipulated variables, a conservative estimate must be taken in how close and how quickly the operation is moved toward the active constraints.  [c.77]

Plate Dryers The plate dryer is an indirect Treated, fully continuous dryer available for three modes of operation atmospheric, gastight, or fall vacuum. The dryer is of vertical design, with horizontal, heated plates mounted inside the housing. The plates are heated by either hot water, steam, or thermal oil, with operating temperatures up to 320°C possible. The product enters at the top and is conveyed through the dryer by a product-transport system consisting of a central-rotating shaft with arms and plows. (See dryer schematic. Fig. 12-78.) The thin product layer (approx. V2 in depth) on the surface of me plates, coupled with frequent product turnover by the conveying system, resalts in  [c.1216]

Octano/—Water Partition Coefficient. The Fragment approach (234—236) has been reviewed (227) and another method similar to the UNIFAC refit for Henry s constant has been proposed. Improved accuracy for many species and the abiUty to correct for temperature effects have been claimed for the newer method.  [c.254]

Rovibrational final-state analysis can also be achieved even for the case of classical nuclei. A product fragment with classical nuclei rotates and vibrates as a classical object. A classical quantum correspondence is adopted, such that this classical object is described by an evolving coherent state. For the case of a diatomic fragment when rotational excitations can be neglected or decoupled, the dynamics can be resolved into quantum states [42]. For low excitations with near equidistant splittings between consecutive vibrational energy levels the harmonic oscillator coherent state provides an excellent basis for obtaining vibrationally resolved cross-sections [43]. As a general approach valid for polyatomic molecular product fragment a multidimensional Prony [44] method has been developed [45], which can produce rovibrationally resolved cross-sections for the case of weak coupling between rotation and vibrational modes.  [c.240]

Fragn em-based methods (also called template-based methods) use an incremental approach. First, they fragment the input structure implementing certain rules. Secondly, the entire, 3D structure is assembled by linking appropriate predefined, 3D structural fragments (,3D templates) taken from a library, Although, fragment-based methods make extensive use of 3D structure information, they need at least a few explicit rules on the fragmentation of input structures, on finding the best matching analogs in the 3D template library, and on properly combining the individual templates with the entire 3D structure.  [c.97]

Screening systems normally use a predefined set of structural fragments called keys. For each key a preliminary (in a pre-process phase) substructure search is performed across the whole structural database. For each database compound a string of bits is constructed. Each bit of this string denotes the presence or absence of a key in the corresponding database compound. The kth bit in the bit-string is set to 1 if the kth key fragment is a substructure of the current database compoimd otherwise the kth bit is set to 0. In the same way during the substructure searching a bit-string of the query structure is constructed. This step is usually very fast since a few himdred isomorphism checks are performed for a set of quite simple structural fragments. Further, the query bit-string is compared with each of the bit-strings from the database. The target compounds are screened as follows each key which is present in the query structure must be present in the target structure (the corresponding bits are compared by using the fast bitwise operation AND, OR, and XOR). If at least one key that is present in the query graph is not present in the target graph, then this compound is pruned from a further processing. In this way a great many structures which are not likely to survive the isomorphism check are pruned early in the screening stage, thus escaping the much more time-consuming backtracking algorithm. This results in a much smaller set of structures being checked for structure isomorphism by means of the backtraddng algorithm. For example, in a typical screening session more than 90% of the database compounds which do not contain the query substructure are removed. Inasmuch as the time dependence of the screening procedure is linear, it decreases the time needed for substructure searching considerably (for example, this approach is 10 to 20 times faster than without the use of screening). Additionally, the screening procedure itself is very fast since it involves only a few isomorphism checks and is performed with the very fast bitwise operations.  [c.302]

A widely used method is fragment-based coding. With this approach, the molecule to be encoded is divided into several substructures that represent the typical information necessary for the task. Many authors have used this method for the automated interpretation of spectra with artificial neural networks [2], in expert systems for structure elucidation [3], with pattern recognition methods [4], and with semi-empirical calculations [5], For example, a desaiptor in the form of a binary vector is used simply to define the presence or absence of functional groups that exhibit important spectral features in the corresponding infrared (IR) spectrum. The main disadvantage of this method is that it imposes a restriction on the number of substructures represented (for the correlation of structure with IR spectra, the number of substructures varies fi om 40 to 720, depending on the user s more or less subjective view of the problem). Affolter et al. [6] showed that a simple assignment of IR-relevant substructures and corresponding IR signals does not describe spectrum-structure correlation to an adequate accuracy. This is mainly due to the effect of the chemical environment on the shape and position of absorption signals.  [c.516]

An enhancement of the simple substructure approach is the Fragment Reduced to an Environment that is Limited (FREL) method introduced by Dubois et al. [7] With the FREL method several centers of the molecule are described, including their chemical environment. By taking the elements H, C, N, O, and halogens into account and combining all bond types (single, double, triple, aromatic), the authors found descriptors for 43 different FREL centers that can be used to characterize a molecule.  [c.516]

H A Scheraga has devised many novel methods with his colleagues for exploring the cor formational space of peptides and proteins [Scheraga 1993]. Each new method is rigorousl evaluated using a standard test molecule, met-enkephalin (H-Tyr-Gly-Phy—Met-OH One method is the build-up approach, in which the peptide is constructed from thre dimensional amino acid templates [Gibson and Scheraga 1987]. Each template correspond to a low-energy region of the Ramachandran map. To explore the conformational space of peptide, a dipeptide fragment is first constructed by joining together all possible pairs c templates available to the first two amino acids. Each dipeptide fragment is minimise and the lowest-energy structures are retained for the next step, in which the third amin acid is connected. The peptide is gradually built up in this way, with energy minimisatio and selection of the lowest-energy structures at each stage.  [c.533]

The alternative is to use a hashed fingerprint, which does not require a predefined fragment dictionary. Rather, an algorithmic approach is used to derive the bitstring, which initially contains all zeros. This method generates all possible linear paths of connected atoms through the molecule containing between 1 and a pre-defined number of atoms (e.g. 8). Eor example, in acetic acid the paths of length zero are just the atoms C and O, the paths of length 1 are CC, C=0 and CO, and of length 2 are CCO and CC=0. Each path defines a pattern of atoms and bonds which serves as the input to a pseudo-random number generator, which produces a set of bits which are then set to the value 1. The hashing process typically sets 4 or 5 bits per pattern. A bitstring might contain 1024 bits, and after all paths  [c.661]

At the outeet of the work described in this thesis, a number of questions were formulated. Given the substantia] benefits of water with respect to the uncatalysed Diels-Alder reaction, the most important question addressed the possibilities of transferring these benefits to the Lewis-acid catalysed reaction. It soon became obvious that this could not easily be achieved, since the majority of Diels-Alder reactants have a negligible tendency to interact with a Lewis-acid catalyst in water. Fortunately, the affinity of a Diels-Alder reactant for Lewis-acids can increase dramatically if the possibility of forming a chelate exists. In Chapter 2 it was demonstrated that, by following this approach, Lewis-acid catalysis of a Diels-Alder reaction in water is feasible. Moreover, it turned out that part of the beneficial effect of water on the uncatalysed Diels-Alder reaction is retained in the Lewis-acid catalysed counterpart. The studies in Chapter 2, and also in Chapter 3, employed a dienophile that has been specifically designed for bidentate binding to the Lewis-acid catalyst. To accomplish this a pyridine ring was fused to a a,p-unsaturated ketone fragment allowing coordination through formation of a 5-membered ring chelate. The encouraging results obtained for the Diels-Alder reaction of this molecule prompted investigation of the possibilities of extending these results to other Diels-Alder reactions. Attempts in this direction are described in this chapter, but first the literature claims of Lewis-acid catalysis of Diels-Alder reactions in water are critically examined.  [c.107]

An alternative approach to peptide sequencing uses a dry method in which the whole sequence is obtained from a mass spectrum, thereby obviating the need for multiple reactions. Mass spec-trometrically, a chain of amino acids breaks down predominantly through cleavage of the amide bonds, similar to the result of chemical hydrolysis. From the mass spectrum, identification of the molecular ion, which gives the total molecular mass, followed by examination of the spectrum for characteristic fragment ions representing successive amino acid residues allows the sequence to be read off in the most favorable cases.  [c.333]

DifficultSepa.ra.tions, Difficult separations, characterized by separation factors in the range 0.95 to 1.05, are frequentiy expensive because these involve high operating costs. Such processes can be made economically feasible by reducing the solvent recovery load (260) this approach is effective, for example, in the separation of m- and -cresol, Hnoleic and abietic components of tall oil (qv), and the production of heavy water (see Deuteriumand TRITIUM, deuterium).  [c.80]

The vast majority of new antibiotics result from screening soil microorganisms or by semisynthetic modification of naturally occurring antibiotics. One alternative approach, termed dkected biosynthesis, involves feeding potential biosynthetic precursors into a fermentation of a known antibiotic in order to produce new components (13,14). This approach was used in the early development stages of the penicillins to obtain penicillin G. Phenylacetic acid was fed to fermentations of Penicillium chiysogenum. Another approach involves bioconversions. A known antibiotic is added to the fermentation of a microorganism that is capable of carrying out a process such as hydroxylation or amination. Modifications of these types can frequentiy be accompHshed with a selectivity that is difficult to obtain by synthetic methods. A procedure called mutasynthesis, fkst reported with regard to new antibiotics related to neomycin (15,16), is sometimes used.  [c.475]

See pages that mention the term Fragment approach : [c.186]    [c.2222]    [c.380]    [c.492]    [c.480]    [c.481]    [c.679]    [c.704]    [c.732]    [c.732]    [c.327]    [c.494]    [c.92]    [c.393]    [c.65]    [c.128]   
Computational chemistry (2001) -- [ c.186 ]