Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy

Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, an...

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Autores principales:	Priyanka Ramesh, Woong-Hee Shin, Shanthi Veerappapillai
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	LC-2/ad cell line drug discovery docking MM-GBSA calculation molecular dynamics cytotoxicity assay Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/a8566ba4770e4e44b5ad36e030ac27ad
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spelling	oai:doaj.org-article:a8566ba4770e4e44b5ad36e030ac27ad2021-11-25T18:40:35ZDiscovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy10.3390/pharmaceutics131117751999-4923https://doaj.org/article/a8566ba4770e4e44b5ad36e030ac27ad2021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1775https://doaj.org/toc/1999-4923Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of RET protein using combined in silico and in vitro strategies. In the present study, screening of 11,808 compounds from the DrugBank repository was accomplished by different hypotheses such as pharmacophore, e-pharmacophore, and receptor cavity-based models in the initial stage. The results from the different hypotheses were then integrated to eliminate the false positive prediction. The inhibitory activities of the screened compounds were tested by the glide docking algorithm. Moreover, RF score, Tanimoto coefficient, prime-MM/GBSA, and density functional theory calculations were utilized to re-score the binding free energy of the docked complexes with high precision. This procedure resulted in three lead molecules, namely DB07194, DB03496, and DB11982, against the RET protein. The screened lead molecules together with reference compounds were then subjected to a long molecular dynamics simulation with a 200 ns time duration to validate the inhibitory activity. Further analysis of compounds using MM-PBSA and mutation studies resulted in the identification of potent compound DB07194. In essence, a cell viability assay with RET-specific lung cancer cell line LC-2/ad was also carried out to confirm the in vitro biological activity of the resultant compound, DB07194. Indeed, the results from our study conclude that DB07194 can be effectively translated for this new therapeutic purpose, in contrast to the properties for which it was originally designed and synthesized.Priyanka RameshWoong-Hee ShinShanthi VeerappapillaiMDPI AGarticleLC-2/ad cell linedrug discoverydockingMM-GBSA calculationmolecular dynamicscytotoxicity assayPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1775, p 1775 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	LC-2/ad cell line drug discovery docking MM-GBSA calculation molecular dynamics cytotoxicity assay Pharmacy and materia medica RS1-441
spellingShingle	LC-2/ad cell line drug discovery docking MM-GBSA calculation molecular dynamics cytotoxicity assay Pharmacy and materia medica RS1-441 Priyanka Ramesh Woong-Hee Shin Shanthi Veerappapillai Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
description	Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of RET protein using combined in silico and in vitro strategies. In the present study, screening of 11,808 compounds from the DrugBank repository was accomplished by different hypotheses such as pharmacophore, e-pharmacophore, and receptor cavity-based models in the initial stage. The results from the different hypotheses were then integrated to eliminate the false positive prediction. The inhibitory activities of the screened compounds were tested by the glide docking algorithm. Moreover, RF score, Tanimoto coefficient, prime-MM/GBSA, and density functional theory calculations were utilized to re-score the binding free energy of the docked complexes with high precision. This procedure resulted in three lead molecules, namely DB07194, DB03496, and DB11982, against the RET protein. The screened lead molecules together with reference compounds were then subjected to a long molecular dynamics simulation with a 200 ns time duration to validate the inhibitory activity. Further analysis of compounds using MM-PBSA and mutation studies resulted in the identification of potent compound DB07194. In essence, a cell viability assay with RET-specific lung cancer cell line LC-2/ad was also carried out to confirm the in vitro biological activity of the resultant compound, DB07194. Indeed, the results from our study conclude that DB07194 can be effectively translated for this new therapeutic purpose, in contrast to the properties for which it was originally designed and synthesized.
format	article
author	Priyanka Ramesh Woong-Hee Shin Shanthi Veerappapillai
author_facet	Priyanka Ramesh Woong-Hee Shin Shanthi Veerappapillai
author_sort	Priyanka Ramesh
title	Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
title_short	Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
title_full	Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
title_fullStr	Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
title_full_unstemmed	Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy
title_sort	discovery of a potent candidate for ret-specific non-small-cell lung cancer—a combined in silico and in vitro strategy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a8566ba4770e4e44b5ad36e030ac27ad
work_keys_str_mv	AT priyankaramesh discoveryofapotentcandidateforretspecificnonsmallcelllungcanceracombinedinsilicoandinvitrostrategy AT woongheeshin discoveryofapotentcandidateforretspecificnonsmallcelllungcanceracombinedinsilicoandinvitrostrategy AT shanthiveerappapillai discoveryofapotentcandidateforretspecificnonsmallcelllungcanceracombinedinsilicoandinvitrostrategy
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Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy

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