Number of hydrogen bond donors

The flic presented contains 11 data items. The header lines arc property names as used by CACTVS [64, 65], and arc sufficiently self-descriptive. For example, E NHDONORS is the number of hydrogen bond donor.s, E SM1LES" is the SMILES string representing the structure of sulfamidc, and E LOGP is the logP value (octanol/water partition coefficient) for this substance. 

Partitioning or cell-based methods provide an absolute measure of the chemical space covered by a collection of compounds. They are based on the definition of a low-dimensional chemistry space, for example, one based on a small number of physicochemical properties such as molecular weight, calculated logP, and number of hydrogen bond donors [45]. Each property defines an axis of the chemistry-space. The range of values for each property is divided into a set of bins, and the combinatorial product of all bins then defines the set of cells or partitions that make up the space. 

There are some very simple heuristic rules concerning cut-offs on molecular weight, number of hydrogen bond donors and acceptors as well as lipophilicity,... 

Oral bioavailability of a drug is primarily dependent upon its rate and extent of drug absorption and systemic clearance. Systemic clearance is primarily composed of hepatic, renal and biliary clearance. The PK properties are in turn directly impacted by the drug s physical properties, such as, log P, log D and pKa. The physical properties are in turn a function of the compound s structure, molecular weight, number of hydrogen bond donors and acceptors, and number of rotatable bonds. Oral bioavailability is the outcome from the dynamic interplay of these factors in the biological system. 

Incorporation of the number of hydrogen-bond donors and acceptors in Eq. 60 resulted in Eqs. 61 and 62. But HCPSA was found to be significantly correlated with HBD and HBA, indicating that it can be used to replace the descriptors related to hydrogen bonds. 

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. 

Property-based descriptors, lipophilicity, molecular flexibility, PSA, and number of hydrogen-bond donors are the main parameters influencing the BBB permeability of compounds. 

Molecular weight is the most significant parameter for predicting the BBB permeability, followed byTPSA, log I , number of hydrogen-bond acceptors, number of hydrogen-bond donors, P-gp substrate probability, and finally the number of rotatable bonds. 

Fig. 6.8 Physiochemical property profiles for the Wyeth screening library (red), the Top 4000 actives (blue) and the selected set (green), (a) MW (b) clogP (c) number of hydrogen bond acceptors (d) number of hydrogen bond donors (e) number of rotatable bonds (f) TPSA. Properties were calculated in MOE [41].

Other descriptors are useful for implementing ADMET constraints upon the ligand derivatives. For example, using fhe CMPNTS descriptor, one can limit the number of rotatable bonds fhe derivative wiU possess. The ATYPE descriptor can be used to limit the number of hydrogen bond donors and acceptors that will be included in fhe derivative. Furthermore, fhe MW descriptor can be used to insure that the generated compounds fall within acceptable size limits. 

Eq. 5 AGbind, free energy of binding /V, [B, number of active site hydrogen bonds formed between substrate and human CYP2B6 HBD, number of hydrogen bond donor. 

Eq. 1 AGbind, free energy of binding log D14, logarithm of the distribution coefficient at pH 7.4 pATa, negative logarithm of the dissociation constant HBD, number of hydrogen bond donors. 

In Lewis et al. s (225) QSAR study, eight CYP2C9 substrates where examined. In this case, it appeared as if the acid dissociation constant pXa, the compounds lipophilicity, and the number of hydrogen bond donor atoms are important features (Eq. 1, Table 8). These suggestions are supported by a good correlation with the binding affinity. 

Eq. 3 Induction fold induction of CYP3A4 in the presence of hGR HBA, number of hydrogen bond acceptors HBD, number of hydrogen bond donor Mr, relative molecular mass. 

Hydrogen bonding number Number of hydrogen bonding donor sites Number of hydrogen bonding acceptor sites... 

This has been shown to work well for a diverse set of libraries (see Note 2) (4). In Fig. 17.3, the offset is calculated for the oxazolidine library for properties related to Lipinski s rule of five (8) the number of hydrogen bond acceptors (HBA), the number of hydrogen bond donors (HBD), the number of non-hydrogen atoms (NHA), and the calculated log P (9). 

Calculated properties were restricted to ClogP <3, the number of rotatable bonds <5, the number of hydrogen bond acceptors (HBA) <4 and the number of hydrogen bond donors (HBD) between 1 and 3. The topological polar surface area (TPSA) was set to <70 A2. In addition, a special feature count excludes structures that are too functionalised (feature rich) or dull (absence of pharmacophoric interaction points). This feature count is the sum of HBA, HBD and the number of five-and six-membered aromatic rings and selection was restricted to fragments with a feature count in the range 4-7. 

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