Aqueous solubility library design

Physico-chemical properties and evaluation of potential safety liabilities are important aspects of the library design process. Predicted properties like hERG liability (45), compound aqueous solubility, etc. (46-48) have been extensively studied and included in various library design strategies (49, 50) as a part of multiple constraints optimisation. We have therefore further extended the ProSAR concept to take the library property profile into account in the design process. Several in-house calculated properties are considered these include a compound novelty check (that checks in in-house and external compound databases to see if the compound is novel), predicted aqueous solubility... 

In summary, poor aqueous solubility is the single physicochemical property that is most likely to be problematical in a combinatorial library. It can be avoided in part by intelligent use of batch-mode solubility calculations. The solubility problem is not simply a technical issue in library design. It is exacerbated by chemistry synthesis considerations and by the timing of the availabihty of combinatorial exemplars. Formulation fixes are available unless the solubility is extremely poor, but these should be avoided as much as possible. Poor permeability is seldom a problem in combinatorial libraries, but is disastrous if present since effectively formulation fixes do not currently exist. 

Effectiveness of designing for adequate aqueous solubility depends on whether chemistry protocol development or chemistry production is rate determining. If chemistry production is rate determining, there will be excess validated protocols relative to library production. This means that protocols can be prioritized as to the attractiveness of the compound solubility profile and the least attractive protocols from a solubility perspective may never be translated into actual library production. However, often protocol development and not library production is the rate-determining step. This eventuality is unfortunate because there is an understandable reluctance to discontinue chemistry synthetic efforts due to poor experimental solubility profile if considerable chemistry effort has already been expended. Consider the following situation. The effort toward library production is 70% complete. The experimental solubility profile is poor. Would you discontinue completion of library synthesis because of poor solubility if 70% of the chemistry effort had already been completed So a key issue becomes how much chemistry experimental effort takes place before exemplars are experimentally profiled in solubility screens ... 

Principal component analysis (PCA) is a mathematical method for dimensionality reduction that allows for multidimensional datasets to be visualized using two- or three-dimensional plots with minimal loss of information [1,2]. When applied in the context of diversity-oriented synthesis, PCA is primarily used to visualize similarities and differences within collections of compounds based on structural and physicochemical parameters, and can be leveraged in library design [3]. Molecular weight, stereocenters, rotatable bonds, hydrophobicity, and aqueous solubility are a few examples of parameters commonly included in such analyses. Herein, we selected 20 structural and physicochemical parameters for analysis based on previously identified correlations of these parameters with oral bioavailability, cell permeability, solubility, and binding selectivity, as well as their ability to distinguish synthetic drugs... 

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