A tool for the post data analysis of screened compounds derived from computer-aided docking scores.

UNLABELLED: A method is described for the analysis of the results obtained from the docking studies applied on a protein target and small molecules chemical compounds as ligands from various sources using different docking tools. We show the use of Dempster Shafer Theory (DST) to select the high ranking top compounds for further analysis and consideration. AVAILABILITY: Application is freely available at http://allamapparao.org/dst/

Background

The number of compounds available for high throughput screening (HTS) has dramatically increased. However, largescale random combinatorial libraries have made limited contributions in the identification of leads in drug discovery projects.Therefore, the concept of ‘drug-likeness’ of compound selections has become a focus in recent years. The low success rate of converting lead compounds into drugs often due to unfavorable pharmacokinetic parameters has sparked a renewed interest in understanding more clearly what makes a compound drug-like [1].

Docking predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using scoring functions [2]. We show the use ofDempster Shafer Theory (DST) [3] on docking results using an example structure with PDB ID: 3CL2 (crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants).

In DST, evidence can be associated with multiple possible events, e.g., sets of events. As a result, evidence in DST can be meaningful at a higher level of abstraction without having to resort to assumptions about the events within the evidential set. Where the evidence is sufficient enough to permit the assignment of probabilities to single events, the Dempster- Shafer model collapses to the traditional probabilistic formulation [4]. Combination rules are the special types of aggregation methods for data obtained from multiple sources.

These multiple sources provide different assessments for the same frame of discernment and Dempster-Shafer theory is based on the assumption that these sources are independent. The requirement for establishing the independence of sources is an important philosophical question.Lianwen Zhang [5] also provides an alternative combination rule to Dempster's rule. With respect to the rule of combination, Zhang points out that Dempster's rule fails to consider how focal elements intersect [5]. To define an alternative rule of combination, he introduces a measure of the intersection of two sets A and B assuming finite sets. This is defined as the ratio of the cardinality of the intersection of two sets divided by the product of the cardinality of the individual sets.

Methodology

Docking, visualization, scoring and selection:

It is important to visualize the docked poses of high-scoring compounds because many ligands are docked in different orientations and may often miss interactions that are known to be important for the target receptor. This sort of study becomes more difficult as the size of the dataset increases. Therefore, an alternative approach is to eliminate unpromising compounds before docking by restricting the dataset to drug-like compounds; by filtering the dataset based on appropriate property and sub-structural features and by performing diversity analysis [6]. Consensus scoring combines information from different scores to balance errors in single scores and improve the probability of identifying ‘true’ ligands [7]. In our study, we have tested five different scoring functions as used in tools such as: (i) GOLD [8]; (ii) Patchdock [9]; (iii) Molegro [10]; (iv) MEDock [11]; (v) AutodockVina [12]. The input for this application is Spread Sheet with an extension of .xls. The spread sheet consists of docking results of various compounds from various docking tools.The uploaded file is parsed and the data is stored in 2D array. We then use DST in a 5 step procedure. The steps used are: (1) Divide the data into 4 classes; (2) get results from Rank Sum Technique; (3) get results from DST unweighted; (4) get results from DST weighted; (5) get results from Zhang Rule. Compounds selected by steps 2 to 5 in the above procedure will be considered for further analysis and investigation in the discovery pipeline.

Output data and analysis

We used 4,347 experimentally determined ligand structures for this study. The target protein structure with PDB ID: 3CL2 was screened against these ligand structures using Molegro to select the optimal binding small molecules using binding scores.The top 35 compounds were further docked using Patchdock, GOLD, MEDock, AutodockVina. Analysis using Dempster Shafer Theory selects compounds having drug bank ID numbers DB02259 and DB01911 as best binding candidates with the protein target and for consideration in further investigations.

Future developments

We plan to include other combination rules such asYager's Rule and Inagaki's Rule in future developments.