Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Srinivasan, Bharath, Zhou, Hongyi, Kubanek, Julia, Skolnick, Jeffrey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
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
_version_ 1782318342099435520
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
work_keys_str_mv AT srinivasanbharath experimentalvalidationoffindsitecombvirtualligandscreeningresultsforeightproteinsyieldsnovelnanomolarandmicromolarbinders
AT zhouhongyi experimentalvalidationoffindsitecombvirtualligandscreeningresultsforeightproteinsyieldsnovelnanomolarandmicromolarbinders
AT kubanekjulia experimentalvalidationoffindsitecombvirtualligandscreeningresultsforeightproteinsyieldsnovelnanomolarandmicromolarbinders
AT skolnickjeffrey experimentalvalidationoffindsitecombvirtualligandscreeningresultsforeightproteinsyieldsnovelnanomolarandmicromolarbinders