Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

Author(s): Geetika Sethi, Gaurav Chopra, Ram Samudrala

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 15 , Issue 8 , 2015

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We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform ( The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery.

Keywords: Druggable proteins, protein drug interactions, protein folds, protein classes, proteome drug discovery, drug discovery benchmark, multiscale modeling, polypharmacology.

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Article Details

Year: 2015
Published on: 27 April, 2015
Page: [705 - 717]
Pages: 13
DOI: 10.2174/1389557515666150219145148
Price: $65

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