Small Molecule Docking from Theoretical Structural Models - Computational Modeling of Biological Systems - page 90

0,8

UNCORRECTLY DOCKED
AND SCORED

0,7

0,6

RMS-based
active recovery

0,5

CORRECTLY DOCKED
UNCORRECTLY SCORED

Score-based
active recovery

0,4

0,3

0,2

CORRECTLY DOCKED
AND SCORED

0,1

0

PDB Model
80-100

Model
60-80

Model
40-60

Model
30-40

Model
25-30

Model
20-25

Model
15-20

Model
10-15

Fig. 9 Expected percentage of success in docking experiments performed using the ensemble
docking approach (both for X-ray and homology models, the later obtained from templates with
different degrees of sequence identities). Recovery rates have been computed as average recovery
rates of four human proteins: renin, thrombin, CDK2, and PTP-1B

even smaller if we focus on protein structures coming from pathogens. Our group
and others [ 12 , 80 ] have suggested that homology models derived from templates
with identity ranges of 30-40% can significantly enrich chemical libraries. These
results allow us to expand dramatically the universe of use of docking techniques
(Fig. 1 ), especially in the case of human proteins with pharmacological interest
(taken from DrugBank database; [ 84 ]), which are covered over 75% when using
homology models up to 30% identity (Fig. 10 ).
Thus, with all the required cautions needed in the use of homology models
for docking purposes (related mostly to the problems in finding good templates
and in determining “a priori” the quality of the model), the use of comparative
models can enlarge dramatically the universe of applicability of small-molecule
docking approaches. Ensemble docking performed on homology models provides
results of similar, or even better quality than those obtained with single crystal
structures, leading to a clear enrichment in the chemical libraries, and producing
poses of good structural quality, even in cases where ligand binding implies
non-negligible changes in protein structure. Altogether ensemble docking from
homology modeling appears as a promising alternative to extend the use of docking
strategies in drug-design pipelines.