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Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

OBJECTIVE: Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras...

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Autores principales: Pathan, Akbar Ali Khan, Panthi, Bhavana, Khan, Zahid, Koppula, Purushotham Reddy, Alanazi, Mohammed Saud, Sachchidanand, Parine, Narasimha Reddy, Chourasia, Mukesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861002/
https://www.ncbi.nlm.nih.gov/pubmed/27217775
http://dx.doi.org/10.2147/OTT.S99671
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author Pathan, Akbar Ali Khan
Panthi, Bhavana
Khan, Zahid
Koppula, Purushotham Reddy
Alanazi, Mohammed Saud
Sachchidanand,
Parine, Narasimha Reddy
Chourasia, Mukesh
author_facet Pathan, Akbar Ali Khan
Panthi, Bhavana
Khan, Zahid
Koppula, Purushotham Reddy
Alanazi, Mohammed Saud
Sachchidanand,
Parine, Narasimha Reddy
Chourasia, Mukesh
author_sort Pathan, Akbar Ali Khan
collection PubMed
description OBJECTIVE: Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. METHODS: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. RESULTS: Interestingly, the designed compounds exhibit a binding preference for the “off” state over “on” state conformation of K-Ras protein. Moreover, the designed compounds’ interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski’s rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values. CONCLUSION: Thus, through the current study, we propose targeting only “off” state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein.
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spelling pubmed-48610022016-05-23 Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches Pathan, Akbar Ali Khan Panthi, Bhavana Khan, Zahid Koppula, Purushotham Reddy Alanazi, Mohammed Saud Sachchidanand, Parine, Narasimha Reddy Chourasia, Mukesh Onco Targets Ther Original Research OBJECTIVE: Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. METHODS: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. RESULTS: Interestingly, the designed compounds exhibit a binding preference for the “off” state over “on” state conformation of K-Ras protein. Moreover, the designed compounds’ interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski’s rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values. CONCLUSION: Thus, through the current study, we propose targeting only “off” state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein. Dove Medical Press 2016-05-02 /pmc/articles/PMC4861002/ /pubmed/27217775 http://dx.doi.org/10.2147/OTT.S99671 Text en © 2016 Pathan et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Pathan, Akbar Ali Khan
Panthi, Bhavana
Khan, Zahid
Koppula, Purushotham Reddy
Alanazi, Mohammed Saud
Sachchidanand,
Parine, Narasimha Reddy
Chourasia, Mukesh
Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title_full Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title_fullStr Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title_full_unstemmed Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title_short Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches
title_sort lead identification for the k-ras protein: virtual screening and combinatorial fragment-based approaches
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861002/
https://www.ncbi.nlm.nih.gov/pubmed/27217775
http://dx.doi.org/10.2147/OTT.S99671
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