The Selection of a Strategy

Mode-of-Action New Lead Generation Maximize Activity 

Each lead should be followed in a way tailored to the specific constraints that surround it. The resources available and the importance of the lead should dictate which strategy to follow. 

Some of the factors affecting the dioice of a strategy are listed below  

Knowledge of area of chemistry or mode/mechanism of action 

Importance of the lead Chemical novelty Biological novelty Amount of activity 

---

An intrinsic decomposition reflects a well-founded relation selected via the Intrinsic Heuristic (Heuristic 4-3), and an extrinsic or logarithmic decomposition reflects a well-founded relation selected via the Extrinsic Heuristic (Heuristic 4-4). The selection of a strategy is a high-level decision that may significantly affect the complexity of the resulting algorithm (but probably not its existence). A reasonable implementation of this synthesis mechanism would accept a preference hint from the specifier. 

Interventions to individual structural members or to parts of an existing masonry structure should be part of a global intervention strategy. The selection of a strategy and, hence, of appropriate intervention techniques (for the repair or strengthening of a structure) is based on a series of investigations and studies that should precede the redesign of the stmcture, as briefly described herein ... 

Often simple strategies for the selection of a good set of PCA scores (for PCR) are applied (a) selection of the first PCA scores which cover a certain percentage of the total variance of X (for instance, 99%) (b) selection of the PCA scores with maximum correlation to y. Application of PCR within R is easy for a given number of components. For an example and a comparison of PCR and PLS, see Section 4.9.1. 

Sometimes it is not necessary to use the selectivity of a chromatographic technique. Sensitive analysis can sometimes be achieved with selective detection in flow injection analysis (FIA). Whilst some of the detectors described below may be appropriate in themselves in favourable cases, in most cases more sophisticated detection regimes are necessary, such as post-injection derivatisation of the analyte. Strategies involving some of the derivatisation methods outlined in Section 4.9.2 may be considered. 

In the selection of a suitable isolation system, a deliberately balanced strategy should be followed. The physical properties of ef-... 

As with any retrosynthetic analysis, once potential strategies are identified, one must address the problems posed by each route. In the present synthesis, such questions arise as Are the planned cyclizations likely to succeed Will the two cyclizations be conducted together or separately In what order will they occur How will the stereochemistry of the methyl group be controlled By what method will the cyclizations be conducted and what will the actual cyclization precursor(s) be How will the precursors be prepared The answers to these questions will help determine the selection of a practical synthetic pathway. 

The selection of a gel matrix should take into account pH and temperature stability, which should be compatible with the characteristics of the target protein. The selection of the most suitable gel should also take into account the main goal to be achieved. If the process is intended to separate proteins from low molar mass solutes (< 5 kDa), a small pore size matrix is recommended, so that proteins are completely excluded from the porous medium. Such a strategy is used for desalting samples. 

If certain amino acids (such as disulfide bonds or crucial amino acids in the hydrophobic core) are indispensable for protein stability, these positions can be changed by site-directed mutagenesis (Proba et al., 1998). To avoid back-mutations during the evolution process or the selection of a residual wild-type contamination, the pool is amplified after each round of ribosome display with a primer that reintroduces the destabilizing mutation. If the mutation is not close to one of the termini, the coding sequence has to be amplified in two parts, which are then reassembled by PCR. Thus, to evolve improved stabilities this strategy first removes known crucial stabilizing factors to select for compensatory mutations at different positions. 

After the selection of a suitable test organism, the strategy of mode of action studies involves basically the testing of the compound under study for its effects on each of the five processes listed above. This requires invariably the study of actively growing cultures or, better, of organisms which are incubated in a medium which supports growth and multiplication. Bactericidal drugs, for example, penicillin... 

Fig. 5.13. Strategy for the selection of a subtilisin mutant (Submut) displayed on phage [66], Calmodulin (CaM) is also displayed and allows the capture of one product of the reaction via the calmodulin binding peptide (CBD).

Fig. 5.15. Strategy for the selection of a phage-displayed polymerase (Pol) [68]. The primertemplate substrate is derivatized with a maleimide reagent and one nucleotide substrate is derivatized with biotin (Bt).The phage is labeled by the product via the maleimide and subsequently captured with immobilised streptavidin (Sv).

Fig. 5.16. Strategy for the selection of a metallo-P-lactamase (Bla) displayed on phage [69], The phage-enzyme is inactivated by extracting the metallic cofactor and captured with an immobilised penicillin substrate. Addition of the metallic cofactor results in the catalytic elution of the phage-enzyme.

HPLC separation of polymers requires the removal of polymer prior to the analysis, low molecular weight SEC can operate without such need, as the polymer will Just be exeluded from the system. SEC presents a quick and easy method development strategy the process involves the selection of a suitable solvent and the use of any small pore size eolumns 50 A and 100 A. All eomponents will elute within a predetermined interval, amounting to one eolumn volume, and the elution volume of any material ean be predicted for a given eolumn provided a ealibration curve is available. 

It has been established that the selection of a proper drug delivery system should comply with the PK and pharmacodynamic properties of the drug to ensure which input strategy would be most beneficial for achieving significant therapeutic advantages. 

---