Simple Molecular Properties

Lead-likeness and drug-likeness were introduced to describe high-quality medicinally relevant compounds and a great deal of effort was devoted over the last 10 

Lipinski et al. at Pfizer [11] analyzed the distribution of physicochemical properties of 2245 drugs from the WDI that have entered clinical trials after excluding natural products and actively transported molecules. They proposed the Rule-of-5 to indicate that poor absorption or permeation is more likely when  

Oxygen (O) and nitrogen (N) atoms count as HBA and -NH or -OH groups add to the number of HBD. Compounds that violate any two of the Rule-of-5 conditions (MW 500, HBA 10, HBD 5, ClogP 5) are unlikely to be oral drugs. 

Kelder et al. [19] have shown that PSA can be used to model oral absorption and brain penetration of drugs that are transported by the transcellular route. A good correlation was found between brain penetration and PSA (n=45, r=0.917). From analyzing a set of 2366 central nervous system (CNS) and non-CNS oral drugs that have reached at least phase 11 clinical trials it was concluded that orally active drugs that are transported passively by the transcellular route should have PSA 120 Al In addition, different PSA distributions were found for CNS and non-CNS drugs. 

The generic term of drug-likeness implies a number of other properties [24] such as aqueous solubility, metabolism, blood-brain barrier penetration and oral absorption which are covered by other chapters in this book. 

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Tab. 17.1 Changes in simple molecular properties between leads and dmgs according to Oprea et al. [21].

Hou, T.J., Wang, J.M., Zhang, W., Xu, X.J. ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules J. Chem. Inf. Model. 2007, 47, 460-3. 

A preliminary and essential step in a QSAR study is to evaluate the database to identify any outliers and hidden patterns, trends, and major groupings. Outliers refer to certain members of the database exhibiting mechanistic behaviors so different that the outlier cannot belong to the bulk of the data. Selecting suitable molecular descriptors, whether they are theoretical or empirical or are derived from readily available experimental characteristics of the structures, is an important step in the development of sound QSAR models. Many descriptors reflect simple molecular properties and thus can provide insight into the physicochemical nature of the activity or property under consideration. 

Fig. 7. Some simple molecular properties which can influence translational overlap in vibrational excitation (see text). Full lines represent initial, and dotted lines the final translational wave...

The experimentalists have most often to rely on theoretical models for the interpretation of their data, both in detailed studies and routine measurements. In order to be useful, these models must be based on conceptually simple molecular properties, of interest for the experimentalist, and contain a manageable number of free parameters. These two criteria are not generally compatible and may require further approximations. The approximations are used to obtain closed expressions the parameters in the analytical formula can be fitted to experimental data. However, due to the approximations involved, the parameters do not directly correspond to molecular properties. 

Lipinski rule of five A set of criteria for predicting the oral bioavailability of a compound on the basis of simple molecular properties (molecular weight. <500 log P. <5 number of hydrogen-bond donors. <5 and number of hydrogen-bond acceptors. < 10). Typically, the criteria are applied to a library to niter structures from the library before any synthesis takes place. Any structure exceeding two or more criteria Is rejected. 

ID Simple filter Simple molecular properties (e.g., molecular weight, molecular volume, element composition, etc.) 10- to 1s... 

A simple molecular property that can be calculated easily and can also be used for shape representation is the composite nuclear potential, denoted by V (r). This 3D molecular function was first compared to 3D molecular electronic densities in a systematic study by Parr and Berk. The VnC ") potential can be determined easily for a large number of nuclear arrangements of large molecules, providing a valid shape representation and a tool for shape comparisons of chemical species. 

Hou TJ, Zhang W, Xia K, Qiao XB, Xu XJ (2004) ADME evaluation in drug diseovery. 5. correlation of caco-2 permeation with simple molecular properties. J Chem Inf Comput Sei... 

Diffusion self diffusion is a simple molecular property that provides quantitative information on the motion of the ions in the liquid and can be easily computed over a long enough simulation time. In particular, the diffusion coefficient, D can be calculated from the mean square displacements using the Einstein relation ... 

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