Validations → Thrombin Enrichment tests

• Method
• Enrichment Analysis
• Docking Results

Method

A collection of 83 Thrombin protein-ligand complexes available from the PDB were used for this study. The protein ligand complex denoted by the PDB code 1O3D([1]) was selected as the query complex molecule. An identical protocol to that followed for the CDK2 active ligands was followed to generate the low energy conformers representing each active thrombin ligand.
The active set (the PDB ligands) together with approximately 900,000 drug-like molecules from the InhibOx CSpace database were filtered, aligned and docked using the DrugFinder platform.  The hits were ranked using the docking score as measured using the PLP scoring function. For comparison, a measure of shape similarity to the query ligand was also calculated for the hits, using the Tanimoto similarity index.

 

Enrichment Analysis

An identical series of analyses as for CDK2 was conducted on the thrombin output lists to analyse the enrichment rates for the different sorting methods. The enrichment rates of the shape measure-based lists were almost identical to that obtained through the CDK2 tests. The first 50 molecules on the list contained 61% of the known actives, with this value increasing to 86% when the top 200 highest scoring molecules were considered. The scoring function-based evaluations, however, did not perform as well and returned enrichment rates around 25% in the top 100 with its value rising to 39% when the top 200 were considered.

The simple PLP scoring function may be unable to adequately account for the directional, polar, interactions which predominate in this site.  A more sophisticated scoring function, such as XScore, may be more suitable and is available within DrugFinder. Nonetheless, an enrichment rate of 25% on a screening run using a database containing almost one million molecules is still of practical utility. Furthermore, analysis of the two  result lists show a relatively small overlap of identical molecules within the first 100 hits, implying that it may be beneficial to combine the hitlists to retrieve a higher percentage of actives.

 

Docking Results

Figure (2) displays the two highest scoring hits obtained from screening CSpace on DrugFinder against thrombin. The known active (i.e. the 1O3D known active) is shown in red, whereas the two hits are coloured in blue.

 

References