Virtual screening combinatorial docking

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

Virtual screening often benefits from an expert bias which helps focus on more desirable results, given in the form of additional information. A point in case is docking under pharmacophore constraints [37] or the concept of relative pharmacophores with a special internal reference point [38]. Yet another application for a directionally biased compound comparison is the selection of chemical reagents where functional attachment points are aligned and pharmacopho-ric features are examined relative to this point of reference by a procedure termed GaP [39]. Other concepts which try to describe combinatorial products in terms of their educts and need a special reference point are shape-based To-pomers [24] and pharmacophore based OsPreys [40]. 

Figure 5.26 Virtual screening of a combinatorial amide library LI targeted towards Candida rugosa lipase using Genetic Optimization for Ligand Docking (GOLD).

Probably more important for the development of docking methods is the introduction of formal structure into this increased search space. If an unstructured compound collection is given, each molecule has to be analyzed independently in a screening experiment. Combinatorial libraries, however, follow a systematic build-up law for synthesizing molecules from a highly limited set of building blocks. This structure can be exploited to drastically reduce the runtime of virtual screening calculations. 

Tuccinardi. T. (2009) Docking-based virtual screening recent developments. Combinatorial Chemistry ej High Throughput Screening, 12, 303-314. 

Tuccinardi, T. (2009) Docking-based virtual screening recent developments. Combinatorial Chemistry ei High Throughput Screening, 12 (3), 303-314. Fan, H Irwin, J.J., Webb, B.M., Klebe,... 

Virtual library A combinatorial library that has no physical existence rather, it exists in a computer or on pjiper. Such libraries cun be generated automatically and. screened against physiocheniicul filters like the "rule of five" or be docked into receptors by use of molcx ular modeling. 

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