Heavy atom count

Figure 11.6 Expressions for ligand efficiency (LE). HAC = heavy atom count, K = 298 K,...

Figure 11.7 Affinity versus heavy atom count for selected compounds. Lines illustrate profiles at fixed ligand efficiency (0.35, 0.30, 0.25) over the range of affinity and heavy atom count. Point A designates an idealized compound with 36 heavy atoms (approximate MW 500 Da ) and affinity 10 nM). Numbers correspond to compounds described in the text.

Based on an empirical formula, the volume check compares the area (3-point) or volume (4-point) of the potential pharmacophore with the heavy atom count for the molecule. This can exclude pharmacophores that have relatively small size when compared to the molecule size, for example a pharmacophore only involving a single residue in a tetrapeptide molecule. Although the estimate is very approximate, using only the heavy atom count, it appears to be a useful filter. 

Select From pubchem.compound Where iupac name Like %aldehyde% And heavy atom count < 20 ... 

While the input query and search type are all that are necessary to perform a sfmcfure search in PubChem, there are numerous choices by which one may narrow the search to smaller subsets of PubChem. For example, one may search only within a previous Entrez search result, or even a previous stmcture search result, or upload a file of ClDs againsf which fhe search is fo be performed. One may filter based on a wide variety of properties, such as molecular weight, heavy atom count, presence or absence of stereochemistry, assay activity, elemental composition, depositor name or category, etc. Most of these subset operations could be accomplished through appropriate Entrez index queries followed by Boolean operations on structure search results however, the structure search tool provides a convenient one-step interface for chemical search refinement. 

In equations (2.3) and (2.4), HA is the heavy atom count. However, LE = affinity HA, being very simple to calculate, is the most widely used measure. 

Remove compounds with heavy atom counts outside 20-45, excluding halogens. 

Another risk factor in compoimd design is molecular size. Kuntz et al. [16] suggested the concept of ligand efficiency (LE), postulating that there should be a limit to what a single atom can contribute to potency, which in turn suggested that potency per heavy atom (or LE) shoidd be optimized. LE is typically defined as potency divided by the number of heavy atoms, that is, LE = plCso/HAC (HAC, heavy atom count). A scaled form may be used that has units of kcal/... 

MW molecular weight HAC heavy atom count PSA polar surface area logD logarithm of octanol-water partitioning coefficient (typically measured at pH 7.4) CL,n unbound intrinsic clearance (apparent intrinsic clearance divided by fraction unbound) log 10-base logarithm In natural logarithm, a) value ofln(lO) RT- IA. 

The heavy-atom count (HAC, heavy atoms = all non-hydrogen atoms) profile shows that FragranceDB contains predominantly very small molecules with an upper boimdary at approximately 21 atoms (Fig. 2.1a). A frequency peak appears at... 

Since chemistry space expands exponentially in proportion to heavy atom count, the Middle Space of molecules between 500 and 1500 Daltons is enormously larger and more diverse than Rule-of-5 space. However, as the chemistry space grows larger, the proportion of molecules that are orally bioavailable becomes minute, and it beeomes imperative to develop a greater understanding of which properties and synthetie strategies can lead to the efficient discovery of orally bioavailable molecules. 

---