H-bond descriptors

G., Folkers, G., Chretien, J. R., Raevsky, 0. A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. f Drug Target. 1998, 2,151-165. 

This chapter describes and classifies H-bond descriptors, and indicates possible areas of their application in QSAR studies and drug design. Similar analyses were presented in previous articles [3-5]. 

Two-dimensional H-bond descriptors are included in Table 6.1. Considering information content, they may be classified as indirect descriptors (no direct link with the H-bonding process), H-bond indicators (atoms having potential H-bond capability) and thermodynamic factors (calculated on the basis of experimental thermodynamic data of H-bonding). 

I 6 H-bonding Parameterization in Quantitative Structure-Activity Relationships di Drug Design Tab. 6.1 Two-dimensional H-bond descriptors. 

PSA is also used as H-bond descriptor to predict various properties of chemicals and drugs. PSA is defined as that part of a molecular surface that arises from oxygen and nitrogen atoms, and also the hydrogens attached to them. Applications of PSA as a QSAR descriptor in correlations with permeability and absorption were carried out first by Van de Waterbeemd et al. [30] and Palm et al. [31]. Clark [32-34] developed this further. Chapter 5 in this book is completely devoted to... 

Three-dimensional H-bond Descriptors 135 Tab. 6.3 Three-dimensional H-bonding parameters and descriptors. 

PSA. Hence, we only mention here that the definition of PSA is similar to that of Na and N. Thus, PSA possesses the same disadvantages when compared to thermodynamic H-bond descriptors. In fact, it has been estimated that there is a strong linear relationship between the calculated static PSA and the calculated dynamic polar surface [32, 33]. A further possible simplification using only the number of H-bond forming atoms and PLS statistics was proposed [35]. Excellent correlahons of PSA with the number of H-bond donors and acceptors were published [35, 36]. 

Application of H-bond Descriptors in QSAR Studies and Drug Design... 

Calculated molecular descriptors including H-bond parameters were used for QSAR studies on different types of permeabiUty. For example, the new H-bond descriptor characterizing the total H-bond ability of a compound, was successfully appUed to model Caco-2 cell permeability of 17 drugs [30]. A similar study on human jejunal in vivo permeabiUty of 22 structurally diverse compounds is described in Ref. [62]. An exceUent one-parameter correlation of human red ceU basal permeabiUty (BP) was obtained using the H-bond donor strength [63] ... 

This means that partition coefficients obtained in one solvent system are related to those determined in another system. Seiler [20] derived the following equation under the assumption that a in Eq. 2.2 is 1 in the absence of hydrogen bonding. In such a way, IH values (H-bond descriptors) have been derived for several functional groups and used in QSAR analysis. 

The charged surface area of hydrogens atoms, called the CSA2u index, and the charged surface area of chlorine atoms, called the CSA2ci index, are two other similar H-bond descriptors defined as ... 

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