Sequential buildup methods

The philosophy that ligands can be constructed piece by piece underlies the sequential buildup methods. The construction need not be linear—in other words, each new piece may be added anywhere on the existing ligand. 

The majority of the sequential buildup procedures use energy-based methods for fragment scoring, although several of the methods use a rule-based approach. 

The site point connection approaches listed in category 2 may be viewed, in principle, as fragment-by-fragment sequential buildup procedures. However, an important difference is that the sequential buildup methods often allow for some conformational adjustment as eadi fragment is added to the ligand. This is not generally done with site point methods. 

There are several advantages to sequential buildup procedures. First, because each fragment is selected based on its ability to contribute to receptor binding, the ligands suggested by these methods should in principle be smaller and more efficient than molecules derived from fragment connection methods. Second, because each piece is added sequentially, it is possible to perform more detailed conformational analyses, leading to fewer misses.  

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Sequential buildup methods Construct a ligand atom by atom, or fragment by fragment. 

Random connection methods A special class of techniques combining some of the features of fragment connection and sequential buildup methods, along with bond disconnection strategies and ways to introduce randomness. 

Figure 5 Schematic piaure of sequential buildup methods...

Of course, there are disadvantages as well. The most important oi these is the problem of crossing what we call dead zones —open spaces of the active site where few receptor contacts are possible. If a sequential buildup method requires each additional fragment to contribute to binding in some significant way, it will then be difficult to cross dead zones from one portion of the active site to another. This problem is depicted in Figure 6 to reach the carbonyl... 

The connection/disconnection methods contain some features ot the sequential buildup procedures, as well as clever ways for altering bond connectivity of the ligand(s) during construction. Several of these techniques also sample the allowed conformational space of the fragments from which ligands are constructed. 

PLA is often coextruded with other polymers to form multilayer structures to enhance its performance properties. For instance, to reduce electrostatic buildup, Rosenbaum et al. [71] disclosed methods for forming biaxially oriented multilayer films, made of one PLA-based layer and two outer layers consisting of PLA and glycerol fatty acid esters, to achieve films with antistatic surfaces. The extruder temperatures used ranged from 170 to 200°C with the takeoff roll set at 60° C. The biaxial orientation took place sequentially, first... 

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