Assembling a Fragment Library - Fragment-Based Drug Discovery - page 38

the maximum affinity of ligands and represents the binding energy per heavy atom in a
molecule. This is equal to the free energy of binding of a ligand to a target protein divided
by the non-hydrogen atom count (NHC) of the ligand [ 3 ] (this may be approximated to
by [- RT ln(IC 50 )]/NHC. Therefore, rather than focusing on the potency of a hit molecule,
fragment-based drug discovery gives access to low molecular weight compounds where
the optimisation process can concentrate on improvements in potency and other desirable
attributes without an immediate concern of increasing molecular weight. Not all fragment
hits will display high ligand efficiency in their interaction with a particular target protein,
so the concept of ligand efficiency is particularly useful in selecting which molecules to
take forward into optimisation.
A key question is how fragments differ from drugs. There is considerable variation in
the literature over the definition of fragments. Commonly fragment molecules are defined
in terms of their chemoinformatic and calculated physical properties and in a similar vein
to Lipinski's rule of five for oral availability of molecules [ 6 ] [molecular weight ≤ 500 Da,

Clog P ≤ 5, hydrogen bond donors (HBD) ≤ 5; hydrogen bond acceptors (HBA) ≤ 10] a

rule of three (molecular weight ≤ 300 Da, Clog P ≤ 3, HBD ≤ 3 with optional additional

criteria of rotatable bonds 60 Å 2 ) has been put forward

for molecules that are used in high-throughput crystallography fragment-based screening
(Table 3.1). [ 7 ] That a variety of different approaches have been adopted for the assembly
of fragment libraries is evidenced by Table 3.2, which provides an overview of the gen-
eral characteristics of fragment libraries from a variety of research groups. The preferred
fragment property profiles of many of these libraries are related to the rule of three. Dur-
ing the generation of a fragment library, such rules for property profiles can be easily
applied to short list fragment-compliant compounds to be purchased from commercial
collections or, alternatively, to be synthesised from virtual libraries. When considering
fragment molecules in the context of screening libraries in general, we have found it
informative to consider the molecules in terms of a molecular weight spectrum ranging
from small solvent molecules at the low end to large drug-like molecules at the high
end. Lead-like molecules occupy a space between the fragment and drug-like molecules
and some groups have also defined 'scaffolds' as occupying this intermediate region
of the spectrum.

≤ 3 and polar surface area ≤

Table 3.1 Comparison of rule of three (RO3) [7] with criteria for compounds
of reduced complexity and for lead-like compounds. [27]

Rule of three Lead-like Reduced complexity

MW < 300 ≤ 460 < 350

Log P (o/w) ≤ 3 ≥ -4 and ≤ 4.2 ≤ 2.2

Log S (water) NA ≥ -5 NA

Rotatable bonds ≤ 3 ≤ 10 ≤ 6

Rings NA ≤ 4 NA

H-bond donors ≤ 3 ≤ 5 ≤ 3

H-bond acceptors ≤ 3 ≤ 9 ≤ 8

Heavy atoms NA NA ≤ 22

TPSA (Å 2 ) ≤ 60 NA NA

NA, not applicable.