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Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders
BACKGROUND: Identification of ligand-protein binding interactions is a critical step in drug discovery. Experimental screening of large chemical libraries, in spite of their specific role and importance in drug discovery, suffer from the disadvantages of being random, time-consuming and expensive. T...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038399/ https://www.ncbi.nlm.nih.gov/pubmed/24936211 http://dx.doi.org/10.1186/1758-2946-6-16 |
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author | Srinivasan, Bharath Zhou, Hongyi Kubanek, Julia Skolnick, Jeffrey |
author_facet | Srinivasan, Bharath Zhou, Hongyi Kubanek, Julia Skolnick, Jeffrey |
author_sort | Srinivasan, Bharath |
collection | PubMed |
description | BACKGROUND: Identification of ligand-protein binding interactions is a critical step in drug discovery. Experimental screening of large chemical libraries, in spite of their specific role and importance in drug discovery, suffer from the disadvantages of being random, time-consuming and expensive. To accelerate the process, traditional structure- or ligand-based VLS approaches are combined with experimental high-throughput screening, HTS. Often a single protein or, at most, a protein family is considered. Large scale VLS benchmarking across diverse protein families is rarely done, and the reported success rate is very low. Here, we demonstrate the experimental HTS validation of a novel VLS approach, FINDSITE(comb), across a diverse set of medically-relevant proteins. RESULTS: For eight different proteins belonging to different fold-classes and from diverse organisms, the top 1% of FINDSITE(comb)’s VLS predictions were tested, and depending on the protein target, 4%-47% of the predicted ligands were shown to bind with μM or better affinities. In total, 47 small molecule binders were identified. Low nanomolar (nM) binders for dihydrofolate reductase and protein tyrosine phosphatases (PTPs) and micromolar binders for the other proteins were identified. Six novel molecules had cytotoxic activity (<10 μg/ml) against the HCT-116 colon carcinoma cell line and one novel molecule had potent antibacterial activity. CONCLUSIONS: We show that FINDSITE(comb) is a promising new VLS approach that can assist drug discovery. |
format | Online Article Text |
id | pubmed-4038399 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40383992014-06-16 Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders Srinivasan, Bharath Zhou, Hongyi Kubanek, Julia Skolnick, Jeffrey J Cheminform Research Article BACKGROUND: Identification of ligand-protein binding interactions is a critical step in drug discovery. Experimental screening of large chemical libraries, in spite of their specific role and importance in drug discovery, suffer from the disadvantages of being random, time-consuming and expensive. To accelerate the process, traditional structure- or ligand-based VLS approaches are combined with experimental high-throughput screening, HTS. Often a single protein or, at most, a protein family is considered. Large scale VLS benchmarking across diverse protein families is rarely done, and the reported success rate is very low. Here, we demonstrate the experimental HTS validation of a novel VLS approach, FINDSITE(comb), across a diverse set of medically-relevant proteins. RESULTS: For eight different proteins belonging to different fold-classes and from diverse organisms, the top 1% of FINDSITE(comb)’s VLS predictions were tested, and depending on the protein target, 4%-47% of the predicted ligands were shown to bind with μM or better affinities. In total, 47 small molecule binders were identified. Low nanomolar (nM) binders for dihydrofolate reductase and protein tyrosine phosphatases (PTPs) and micromolar binders for the other proteins were identified. Six novel molecules had cytotoxic activity (<10 μg/ml) against the HCT-116 colon carcinoma cell line and one novel molecule had potent antibacterial activity. CONCLUSIONS: We show that FINDSITE(comb) is a promising new VLS approach that can assist drug discovery. BioMed Central 2014-04-26 /pmc/articles/PMC4038399/ /pubmed/24936211 http://dx.doi.org/10.1186/1758-2946-6-16 Text en Copyright © 2014 Srinivasan et al.; licensee Chemistry Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. |
spellingShingle | Research Article Srinivasan, Bharath Zhou, Hongyi Kubanek, Julia Skolnick, Jeffrey Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title | Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title_full | Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title_fullStr | Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title_full_unstemmed | Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title_short | Experimental validation of FINDSITE(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
title_sort | experimental validation of findsite(comb) virtual ligand screening results for eight proteins yields novel nanomolar and micromolar binders |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038399/ https://www.ncbi.nlm.nih.gov/pubmed/24936211 http://dx.doi.org/10.1186/1758-2946-6-16 |
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