Dataset Information

Fingerprinting CANDO: Increased Accuracy with Structure- and Ligand-Based Shotgun Drug Repurposing.

ABSTRACT: We have upgraded our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing by including ligand-based, data fusion, and decision tree pipelines. The goal of shotgun drug repurposing is to screen and rank every existing human use drug or compound for every disease/indication. The first version of CANDO implemented a structure-based pipeline that modeled interactions between compounds and proteins on a large scale, generating compound-proteome interaction signatures used to infer the similarity of drug behavior; the new pipelines accomplish this by incorporating molecular fingerprints and the Tanimoto coefficient. We obtain improved benchmarking performance with the new pipelines across all three evaluation metrics used: average indication accuracy, pairwise accuracy, and coverage. The best performing pipeline achieves an average indication accuracy of 19.0% at the top10 cutoff, compared to 11.7% for v1, and 2.2% for a random control. Our results demonstrate that the CANDO drug recovery accuracy is substantially improved by integrating multiple pipelines, thereby enhancing our ability to generate putative therapeutic repurposing candidates, and increasing drug discovery efficiency.

SUBMITTER: Schuler J

PROVIDER: S-EPMC6812124 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Fingerprinting CANDO: Increased Accuracy with Structure- and Ligand-Based Shotgun Drug Repurposing.

Schuler James J Samudrala Ram R

ACS omega 20191009 17

We have upgraded our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun drug repurposing by including ligand-based, data fusion, and decision tree pipelines. The goal of shotgun drug repurposing is to screen and rank every existing human use drug or compound for every disease/indication. The first version of CANDO implemented a structure-based pipeline that modeled interactions between compounds and proteins on a large scale, generating compound-proteome interaction ...[more]

PMID: 31656912

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Project description:The COVID-19 pandemic has accelerated the need to identify new antiviral therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device. We modelled Remdesivir and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of lead compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. We also demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Lastly, we employed an in vitro polymerization assay to demonstrate that these compounds directly inhibit the RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2. Together, our data reveal that our QUBO model performs accurate comparisons (BMS-986094) that differed from those predicted by Tanimoto (different forms of vitamin B12); all compounds inhibited replication of SARS-CoV-2 via direct action on RdRP, with both models being useful. While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Dataset Information

Fingerprinting CANDO: Increased Accuracy with Structure- and Ligand-Based Shotgun Drug Repurposing.

Publications

Fingerprinting CANDO: Increased Accuracy with Structure- and Ligand-Based Shotgun Drug Repurposing.

Similar Datasets

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