Polar surface area , distributions

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. 

Roche datasets, (b) Cumulative topological polar surface area (A ) distributions of compounds in the Gasteiger [33] and Roche datasets, (c) Cumulative chemical complexity distributions of compounds in the Gasteiger [33] and Roche datasets, (d) Cumulative rotatable bond count distributions of compounds in the Gasteiger [33] and Roche datasets. 

Figure 9.3 Polar surface area (PSA) distributions for ActiveSight, ChemBridge and Maybridge fragment libraries.

There are, in addition to these simple functional group filters, a number of property-based filters that may be applied. These fdters take the form of calculated metrics, such as the Lipinski Rule of Five (LRoF Hydrogen-bond donors. Hydrogen-bond acceptors, Lipophilicity, Molecular weight). Solubility, total Polar Surface Area (tPS A), Blood-brain-barrier (BBB) Permeability, calculated metabolic filters (cADMET Absorption-Distribution-Metabolism-Excretion-Toxicity) and Bioavailability. 

Figure 6.1. Distribution of polar surface area for 776 orally administered CNS drugs (black bars) and for 1590 orally administered non-CNS drugs (white bars) that have reached clinical phase II efficacy studies (35).

FIGURE 12.1 Distribution of the polar surface area (A) for drugs that have reached at least Phase 11 efficacy studies. Panel A 776 orally administered CNS drugs. Panel B 1,590 orally administered non-CNS drugs. ... 

Fig. 22.4 Molecular properties can be divided into experimental (subdivided into biological and physicochemical) and in silico (subdivided into structural and substructural) properties, physicochemical and biological properties. Examples of experimental data are IC50 (binding affinity), MIC (antibacterial minimum inhibition concentration), LD50 (lethal dose), Vd (volume of distribution), F% (bioavailability), pKg (ionization constant), log P (partition coefficient from shake flask determination), log kn,(lipophilicity from HPLC measurement), A (hydrogen bond capability), solubility. Examples of calculated properties, either for whole molecule or for substituents or buildings blocks, are MW (molecular weight), MR (molar refractivity), molecular volume, PSA (polar surface area), HA (number of H-bond acceptors), HD (number of H-bond donors), CLOGP (calculated log P values), L (substituent length), B5 (substituent width), cr (Hammett constant), F, R (field and resonance parameters), TT (Hansch constant), f (hydrophobic fragmental constant).

Large-scale distributed computing of chemical properties has been carried out using ChemStar, wherein the Topological Polar Surface Area (TPSA) property of 18 million compounds was studied using Java Remote Method Invocation (JAVA RMI) [51],... 

Drug pff. LogP LogD Polar surface area (A ) Fraction unbound Volume distribution (1/1%)... 

Figure 11.1 Distribution of molecular weight (MW), calculated logP (clogP), and polar surface area (PSA) for the MLSMR collection (March 2014, A/ = 404 732).

---