Cargando…
Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer
The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib’s downsides, the current study is expedited to search for energetically stable and optimize...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10221949/ https://www.ncbi.nlm.nih.gov/pubmed/37241785 http://dx.doi.org/10.3390/molecules28104044 |
_version_ | 1785049578988371968 |
---|---|
author | Ejaz, Syeda Abida Aziz, Mubashir Fawzy Ramadan, Mohamed Fayyaz, Ammara Bilal, Muhammad Sajjad |
author_facet | Ejaz, Syeda Abida Aziz, Mubashir Fawzy Ramadan, Mohamed Fayyaz, Ammara Bilal, Muhammad Sajjad |
author_sort | Ejaz, Syeda Abida |
collection | PubMed |
description | The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib’s downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of −41.48 and −29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of −37.92 and −38.5 kJ/mol against ERBB and −41.2 and −46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies. |
format | Online Article Text |
id | pubmed-10221949 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102219492023-05-28 Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer Ejaz, Syeda Abida Aziz, Mubashir Fawzy Ramadan, Mohamed Fayyaz, Ammara Bilal, Muhammad Sajjad Molecules Article The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib’s downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of −41.48 and −29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of −37.92 and −38.5 kJ/mol against ERBB and −41.2 and −46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies. MDPI 2023-05-12 /pmc/articles/PMC10221949/ /pubmed/37241785 http://dx.doi.org/10.3390/molecules28104044 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ejaz, Syeda Abida Aziz, Mubashir Fawzy Ramadan, Mohamed Fayyaz, Ammara Bilal, Muhammad Sajjad Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title | Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title_full | Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title_fullStr | Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title_full_unstemmed | Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title_short | Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer |
title_sort | pharmacophore-based virtual screening and in-silico explorations of biomolecules (curcumin derivatives) of curcuma longa as potential lead inhibitors of erbb and vegfr-2 for the treatment of colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10221949/ https://www.ncbi.nlm.nih.gov/pubmed/37241785 http://dx.doi.org/10.3390/molecules28104044 |
work_keys_str_mv | AT ejazsyedaabida pharmacophorebasedvirtualscreeningandinsilicoexplorationsofbiomoleculescurcuminderivativesofcurcumalongaaspotentialleadinhibitorsoferbbandvegfr2forthetreatmentofcolorectalcancer AT azizmubashir pharmacophorebasedvirtualscreeningandinsilicoexplorationsofbiomoleculescurcuminderivativesofcurcumalongaaspotentialleadinhibitorsoferbbandvegfr2forthetreatmentofcolorectalcancer AT fawzyramadanmohamed pharmacophorebasedvirtualscreeningandinsilicoexplorationsofbiomoleculescurcuminderivativesofcurcumalongaaspotentialleadinhibitorsoferbbandvegfr2forthetreatmentofcolorectalcancer AT fayyazammara pharmacophorebasedvirtualscreeningandinsilicoexplorationsofbiomoleculescurcuminderivativesofcurcumalongaaspotentialleadinhibitorsoferbbandvegfr2forthetreatmentofcolorectalcancer AT bilalmuhammadsajjad pharmacophorebasedvirtualscreeningandinsilicoexplorationsofbiomoleculescurcuminderivativesofcurcumalongaaspotentialleadinhibitorsoferbbandvegfr2forthetreatmentofcolorectalcancer |