Hydrogen bond descriptor-based approaches

Artursson, P. and McFarland, J.W. (2002) A novel approach for prediction of intestinal absorption of drugs in humans based on hydrogen bond descriptors and structural similarity. Quantitative Structure—Activity Relationships, 20, 402 113. 

One of the simplest and most common ways to evaluate a molecule for ADME properties is a qualitative examination of its basic descriptor values such as molecular weight (MW), ClogP for lipophilicity, polar surface area (PSA), counts of hydrogen bond donors and acceptors (HBD, HBA), and count of rotatable bonds (RB). This type of approach popularized by Lipinski s famous Rule of 5 was published a decade ago [6]. Lipinski et al. established cutoffs for MW (500), ClogP (5), HBA (10), and HBD (5). These cutoffs were based on the 90th percentile of distributions of molecules in the World Drug Index having USAN or INN names. The Rule of 5 considers a violation of any two of these cutoffs to be an alert for poor absorption or permeability. 

However, the CIMI/bc descriptors are relatively simplistic as they did not recognize differences between some important atom types (e.g., halogens). Based on the results of ARD approach, the octanol-water partition coefficient (log P), the molecular flexibility (number of rotatable bonds), the PSA, and the number of hydrogen bond donors were the most important descriptors in the model. None of the descriptors were significantly correlated with each other except log P and PSA for which the correlation was not high ( 0.5). The molecular weight was found to be the least significant descriptor in the model. 

Another approach based on statistical analysis of residue-specific protein-ligand interaction terms is named TScore [138[. Here, individual protein-ligand interactions are evaluated for each residue within 8 A around the ligand. Force field-based descriptors are replaced by Chemscore [96] and PLP [139] terms for hydrogen bonds, lipophilicity, and steric contact. Its application to a series of factor Xa inhibitors resulted in a predictive tailored scoring function vdth 52 selected descriptors after PLS analysis q = 0.(>4, r = 0.83). This concept allows a visual interpretation of... 

Finally, there is one particular topological descriptor that should be mentioned because it has found considerable utility in a number of studies. This property, originally called a chemically intuitive molecular index by its inventor, Frank Burden, is based on a modified molecular adjacency matrix. The approach was extended by Pearlman " to take account of atomic charge, polarisability and hydrogen bonding ability, properties which are termed BCUT descriptors. BCUTs are available in a number of software packages and in addition to their utility in QSAR modelling, they have been shown to be useful measures of chemical similarity. 

Among the approaches proposed so far, we recall here single-parameter models [102-111, 115, 118-120, 122, 123, 125, 126, 129], and multi-parametric correlation equations (either based on the combination of two or more existing scales or on the use of specific parameters to account for distinct types of effects) [112, 113, 116, 117, 121, 124]. Additional popular models are the Abraham s scales of solute hydrogen-bond acidity and solute hydrogen-bond basicity [127, 128], and the Catalan et al. solvatochromic scales [130,132, 133]. Methods based on quantitative stmcture-property relationships (QSPR) with solvent descriptors derived from the molecular structure [131, 134], and on principal component analysis (PCA) [135, 136] have been also proposed. An exhaustive review concerning the quantification of the solvent polarity has been recently published [138-140], including a detailed list of solvent scales, interrelations between parameters and statistical approaches. 

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