Hard filters

Hard filter elimination. The list of solution scores is used for the elimination of solutions with values outside the range allowed by the corresponding active hard filters defined by the user. 

The resulting library consisted of 250 compounds representing different compromises between the two conflicting objectives supplied. Figure 3.5 presents a plot of the Pareto-approximation proposed by the software library (circles connected by line). Each of the remaining circles represents a solution from the initial population set after the hard filtering process. The x-axis represents similarity to ER-a ligands and the -axis dissimilarity (1-similarity)... 

Hard filters are the most stringent in-silico filters and are used to shape the property profile of screening or combinatorial libraries and to prune hit lists from primary screening. They are derived from ID and 2D molecular properties (molecular weight, number of H-bond donors/acceptors, number of rotatable bonds, and so forth) and, as is described below, they are commonly used to reduce the number of false positive hits and to favor lead-like or drug-like chemotypes. 

Whereas hard filters can be considered to be knowledge-driven, soft filters are the result of a data-driven approach. A quantitative structure-activity or structure-property relationship (QSAR/QSPR) is established to predict a property from a set of molecular descriptors. Examples are the above-mentioned in-silico prediction tools for frequent hitters [27] and drug-likeness [41,42] additional models for ADM E properties are described below. 

For diagnostic purposes, the following procedure of the Brdicka filtrate test is to be recommended. Add 0.4 ml of fresh blood serum to 1 ml 0.1 M KOH and allow to stand for 45 min. Precipitate the proteins at room temperature by the addition of 1 ml of 20% sulphosalicylic acid. After 10 min, filter the precipitate through a hard filter paper and add 0.5 ml of clear filtrate to 5 ml of buffered hexamino-cobalt(III) solution (10 M in 0.1 M NH4CI, 1 M NH3). Compare the increase in the height of the wave of the serum filtrate from the patients with the average height of that obtained from 10 or 20 normal humans. 

Hann et al. used a similar, multilevel approach when pooling compounds for HTS. These authors applied three types of filters. Basic filters were used to remove molecules with non-drug-like features. Next functional group-based hard filters were utilized... 

I. Aluminum hydroxide (C.P. or better) is dissolved with moderate heating in sodium iQ droxide solution (saturated in the cold) until saturation is attained. The solution is diluted with water to a density of 1.1, suction-filtered through hard filter paper, and stored for two weeks in a closed vessel. The mother liquor is decanted from the precipitate of Ai(OH) 3 formed. The residue is digested for several days with cold water and then washed with hot water until no alkaline reaction is detectable with litmus. The product is dried first over CaClg, then over PsOg. The entire preparation is carried out in Pyrex glassware. 

The simplicity of this approach hides a number of shortcomings. As noted above, hard filters impose an artificially harsh distinction between compounds in the scenario above, would it be appropriate to reject a compound that was ideal in all properties, except that the inhibition of the target at 10 pM was only 78% ... 

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