Cargando…

Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants

Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively f...

Descripción completa

Detalles Bibliográficos
Autores principales: Kaur, Kuldeep, Devi, Bharti, Agrawal, Vishal, Kumar, Rajnish, Sandhir, Rajat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9667835/
https://www.ncbi.nlm.nih.gov/pubmed/36404953
http://dx.doi.org/10.1007/s42485-022-00098-x
_version_ 1784831789885292544
author Kaur, Kuldeep
Devi, Bharti
Agrawal, Vishal
Kumar, Rajnish
Sandhir, Rajat
author_facet Kaur, Kuldeep
Devi, Bharti
Agrawal, Vishal
Kumar, Rajnish
Sandhir, Rajat
author_sort Kaur, Kuldeep
collection PubMed
description Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively for treatment of Alzheimer’s disease, Huntington’s disease, glaucoma, and in hippocampal neurons from aged mice. However, phytochemicals have received far little attention in studies involving development of potential CYP46A1 inhibitors. Thus, in the present study phytoconstituents from Indian traditional medicinal plants; Bacopa monnieri, Piper longum, and Withania somnifera, were virtually screened for interaction with CYP46A1 using computational tools. Out of three plants, six molecules from P. longum and three molecules from W. somnifera were shortlisted to study interactions with CYP46A1 based on the physio-chemical parameters. Fargesin, piperolactam A and coumaperine from P. longum showed the higher binding affinity and the values were − 10.3, − 9.5, − 9.0 kcal/moles respectively, whereas, withaferin A from W. somnifera had a binding affinity of − 12.9 kcal/mol. These were selected as potential modulators as they exhibited suitable interactions with active site residues; Tyr109, Leu112, Trp368, Gly369, and Ala474. The selected molecules were further subjected to molecular dynamics simulation. Further, the pharmacological properties of molecules were also predicted using ADMET calculator and the data revealed that all the selected compounds had good absorption as well as solubility characteristics. In addition, sesamin, fargesin, piperolactam A, and coumaperine had minimal or no toxic effects. Thus, the study successfully identified compounds from Indian medicinal plants that may serve as potential inhibitors of CYP46A1 or base structures to design novel CYP46A1 inhibitors, which may be effective in treating neurological conditions involving perturbed cholesterol homeostasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42485-022-00098-x.
format Online
Article
Text
id pubmed-9667835
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer Nature Singapore
record_format MEDLINE/PubMed
spelling pubmed-96678352022-11-16 Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants Kaur, Kuldeep Devi, Bharti Agrawal, Vishal Kumar, Rajnish Sandhir, Rajat J Proteins Proteom Original Article Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively for treatment of Alzheimer’s disease, Huntington’s disease, glaucoma, and in hippocampal neurons from aged mice. However, phytochemicals have received far little attention in studies involving development of potential CYP46A1 inhibitors. Thus, in the present study phytoconstituents from Indian traditional medicinal plants; Bacopa monnieri, Piper longum, and Withania somnifera, were virtually screened for interaction with CYP46A1 using computational tools. Out of three plants, six molecules from P. longum and three molecules from W. somnifera were shortlisted to study interactions with CYP46A1 based on the physio-chemical parameters. Fargesin, piperolactam A and coumaperine from P. longum showed the higher binding affinity and the values were − 10.3, − 9.5, − 9.0 kcal/moles respectively, whereas, withaferin A from W. somnifera had a binding affinity of − 12.9 kcal/mol. These were selected as potential modulators as they exhibited suitable interactions with active site residues; Tyr109, Leu112, Trp368, Gly369, and Ala474. The selected molecules were further subjected to molecular dynamics simulation. Further, the pharmacological properties of molecules were also predicted using ADMET calculator and the data revealed that all the selected compounds had good absorption as well as solubility characteristics. In addition, sesamin, fargesin, piperolactam A, and coumaperine had minimal or no toxic effects. Thus, the study successfully identified compounds from Indian medicinal plants that may serve as potential inhibitors of CYP46A1 or base structures to design novel CYP46A1 inhibitors, which may be effective in treating neurological conditions involving perturbed cholesterol homeostasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42485-022-00098-x. Springer Nature Singapore 2022-11-16 2022 /pmc/articles/PMC9667835/ /pubmed/36404953 http://dx.doi.org/10.1007/s42485-022-00098-x Text en © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Original Article
Kaur, Kuldeep
Devi, Bharti
Agrawal, Vishal
Kumar, Rajnish
Sandhir, Rajat
Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title_full Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title_fullStr Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title_full_unstemmed Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title_short Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants
title_sort identification of potential inhibitors of brain-specific cyp46a1 from phytoconstituents in indian traditional medicinal plants
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9667835/
https://www.ncbi.nlm.nih.gov/pubmed/36404953
http://dx.doi.org/10.1007/s42485-022-00098-x
work_keys_str_mv AT kaurkuldeep identificationofpotentialinhibitorsofbrainspecificcyp46a1fromphytoconstituentsinindiantraditionalmedicinalplants
AT devibharti identificationofpotentialinhibitorsofbrainspecificcyp46a1fromphytoconstituentsinindiantraditionalmedicinalplants
AT agrawalvishal identificationofpotentialinhibitorsofbrainspecificcyp46a1fromphytoconstituentsinindiantraditionalmedicinalplants
AT kumarrajnish identificationofpotentialinhibitorsofbrainspecificcyp46a1fromphytoconstituentsinindiantraditionalmedicinalplants
AT sandhirrajat identificationofpotentialinhibitorsofbrainspecificcyp46a1fromphytoconstituentsinindiantraditionalmedicinalplants