Leadlike properties

By applying the results from Table 2.3 to the work presented in Tables 2.1 and 2.2, we can further examine the proportion of high-activity and low-activity molecules with leadlike properties, that is, MW < 460, LogP —4 to 4.2, ELogSw > —5, RTB < 10, RNG < 4, HDO < 5 and HAG < 9 [62]. There are 21.7% HAMs and 41% LAMs that meet the computational leadlike criteria (Table 2.4). The probability of finding HAMs in WOMBAT is rather low in the leadlike space, and is higher outside the R05-compliant space (see Hi/Lo ratios in Table 2.4). While this may not hold true across all chemical space, it does strengthen the conclusion that HAMs are decorated with... 

Druglike or leadlike properties, no toxicophores Confirmed structure and purity... 

If multiple HTS actives of the same chemical family are to some extent leadlike (vide infra), they become a lead series, that is, structures that are amenable for further chemistry optimization and exhibit favorable patent situation [18, 19]. Lead series are further queried and derivatized in order to derive analogs with the appropriate blend of pharmacodynamic and pharmacokinetic properties. 

Tab. 2.4 The proportion of HAMs and LAMs that are leadlike and R05 compliant. The Hi/Lo ratio is obtained by dividing HAMs to LAMs and can be seen as a rough indicator of the probability of finding high-activity molecules in the chemical property space defined by leadlike and R05 criteria, respectively...

The design of leadlike combinatorial libraries is an approach of more recent interest. A lower molecular weight starting point is advantageous, in that bulk can be added for po-tency/selectivity/properties without exceeding "rule of 5 parameters for orally absorbed drugs otherwise a more labor-intensive step may be needed to identify a smaller active part of the hit. The properties required of library compounds intended to provide leads suitable for further optimization, that may be rather different from final optimized leads, has been reviewed (95),... 

Properties Bluish-white, leadlike metal. D 11.85, mp 302C, bp 1457C, oxidizes in air at room temperature. Soluble in nitric and sulfuric acids insoluble in water but readily forms soluble compounds when exposed to air or water. 

Table 1.1 Comparison of properties typically used for leadlikeness and druglikeness criteria.

Rishton, G.M. (2008) Molecular diversity in the context of leadlikeness compound properties that enable effective biochemical screening. Current Opinion in Chemical Biology, 12, 340-351. 

Figure 2.3a shows the plot of log(BB) (log brarniblood ratio) versus calculated 2D PSA. The compounds compliant with the CNS leadlike filters are emiched with respect to higher log(BB) values. Classification of the same compound set into three groups, CNS + + (log(BB) >0), CNS+ (-0.5

In addition to the two major categories of LEVS approaches, similarity searching and compound classification, database filtering techniques should also be added to the virtual screening spectrum. Rule-based filters that screen databases for compounds with desired (e.g., drug- or leadlike) or undesired (toxicity and instability) molecular properties are widely used, not to identify individual active compounds but rather to reduce the size of screening databases as much as possible for further studies using more sophisticated methods. 

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