Advisory Committee on Health Effects of Endocrine Disruptors
The Supplement II to the Intermediary Report
1.1.3

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3. Progress of study and results obtained
(1) Screening
(a) In silico screening
The high-throughput three-dimensional structure-activity relationship (SAR) technique in silico was studied for screening based on the binding capacity to the receptor molecule of the substance in question. The automatic docking model for estrogen receptor α (ERα), shown to be useful in preliminary studies, was improved for virtual screening.
The screening sorted about 2,000 candidates of ER-binding agents out of some 200,000 substances. The calculation technique is under further refinement. Estimation of the relative binding capacity with 176-estradiol is now being tested.
Kanno's group developed an in silico docking calculation technique for ER6 and is now comparing the method involving ERα.
The background of the in silico technique presently used should be mentioned here. Intensive preliminary investigation showed that the docking technique, involving calculation of receptor-ligand interaction, is preferable to various methods based on ligand structure analysis and regression models, such as the commonly used (by the U.S. EPA, for example) CoMFA technique.
The latter method is based on statistical analysis related to ligand molecule geometry deduced from observation of ligand activity. This permits examination of systems containing receptors of unknown structure. On the other hand, the predictive performance of the method depends on the "tutor" compounds used to produce statistical data. In other words, it is difficult to apply to molecules structurally dissimilar to the tutor compounds.
In contrast, the docking technique needs no tutor compound (although some tutors are used presently), and therefore has no structural limits about ligands considered, although it has its own limitations, such as the need for the knowledge of the structure of the ligands, the complexity and incompleteness of the theory used in calculating the interaction, and tedious calculations. Comparison of computational predictions with actual observations showed that this technique is a practical one for the screening in which pseudo-positives are tolerated.

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