E-pharmacophore modelling, virtual screening, molecular dynamics simulations and in-silico ADME analysis for identification of potential E6 inhibitors against cervical cancer

Avinash Kumar, Ekta Rathi, Suvarna G. Kini

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Abstract

DNA of high-risk HPV 16 and 18 has been found to be associated with nearly 90% cases of cervical cancer. The viral E6 and E7 genes of HPV are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target. In the present work, a six-point e-pharmacophore model (AADHRR)was built and used for virtual screening of a focussed library of 5900 compounds, which was downloaded from ZINC 15 database. The pharmacophore-based virtual screening filtered out top 1200 hits, based on fitness score. Molecular docking tool like GLIDE was used for structure-based virtual screening in the HTVS (high-throughput virtual screening)mode as it is very fast and less computational power is required. 130 compounds (based on dock score)obtained from HTVS docking were further filtered to 40 hits employing docking in standard precision mode, which is computationally less demanding than docking in extra precision (XP)mode. Finally, best ten hits were identified using docking in XP mode. ZINC14761180 was the best identified hit which was put for molecular dynamics simulations studies and it suggests that ZINC14761180-E6 complex was quite stable for the whole 15ns simulation period. Interestingly, this compound bears 90% similarity with luteolin which has been reported as E6/E7 oncogene inhibitor. QikProp results suggested that identified hits have drug like physico-chemical properties. Present work re-affirms the previous finding that E6AP binding pocket on E6 protein is druggable. These identified hits may act as new leads for inhibition of E6 against cervical cancer.

Original languageEnglish
Pages (from-to)299-306
Number of pages8
JournalJournal of Molecular Structure
Volume1189
DOIs
Publication statusPublished - 05-08-2019

Fingerprint

Molecular dynamics
Screening
Computer simulation
Throughput
Luteolin
Docks
Chemical properties
Genes
DNA
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Spectroscopy
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "E-pharmacophore modelling, virtual screening, molecular dynamics simulations and in-silico ADME analysis for identification of potential E6 inhibitors against cervical cancer",
abstract = "DNA of high-risk HPV 16 and 18 has been found to be associated with nearly 90{\%} cases of cervical cancer. The viral E6 and E7 genes of HPV are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target. In the present work, a six-point e-pharmacophore model (AADHRR)was built and used for virtual screening of a focussed library of 5900 compounds, which was downloaded from ZINC 15 database. The pharmacophore-based virtual screening filtered out top 1200 hits, based on fitness score. Molecular docking tool like GLIDE was used for structure-based virtual screening in the HTVS (high-throughput virtual screening)mode as it is very fast and less computational power is required. 130 compounds (based on dock score)obtained from HTVS docking were further filtered to 40 hits employing docking in standard precision mode, which is computationally less demanding than docking in extra precision (XP)mode. Finally, best ten hits were identified using docking in XP mode. ZINC14761180 was the best identified hit which was put for molecular dynamics simulations studies and it suggests that ZINC14761180-E6 complex was quite stable for the whole 15ns simulation period. Interestingly, this compound bears 90{\%} similarity with luteolin which has been reported as E6/E7 oncogene inhibitor. QikProp results suggested that identified hits have drug like physico-chemical properties. Present work re-affirms the previous finding that E6AP binding pocket on E6 protein is druggable. These identified hits may act as new leads for inhibition of E6 against cervical cancer.",
author = "Avinash Kumar and Ekta Rathi and Kini, {Suvarna G.}",
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N2 - DNA of high-risk HPV 16 and 18 has been found to be associated with nearly 90% cases of cervical cancer. The viral E6 and E7 genes of HPV are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target. In the present work, a six-point e-pharmacophore model (AADHRR)was built and used for virtual screening of a focussed library of 5900 compounds, which was downloaded from ZINC 15 database. The pharmacophore-based virtual screening filtered out top 1200 hits, based on fitness score. Molecular docking tool like GLIDE was used for structure-based virtual screening in the HTVS (high-throughput virtual screening)mode as it is very fast and less computational power is required. 130 compounds (based on dock score)obtained from HTVS docking were further filtered to 40 hits employing docking in standard precision mode, which is computationally less demanding than docking in extra precision (XP)mode. Finally, best ten hits were identified using docking in XP mode. ZINC14761180 was the best identified hit which was put for molecular dynamics simulations studies and it suggests that ZINC14761180-E6 complex was quite stable for the whole 15ns simulation period. Interestingly, this compound bears 90% similarity with luteolin which has been reported as E6/E7 oncogene inhibitor. QikProp results suggested that identified hits have drug like physico-chemical properties. Present work re-affirms the previous finding that E6AP binding pocket on E6 protein is druggable. These identified hits may act as new leads for inhibition of E6 against cervical cancer.

AB - DNA of high-risk HPV 16 and 18 has been found to be associated with nearly 90% cases of cervical cancer. The viral E6 and E7 genes of HPV are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target. In the present work, a six-point e-pharmacophore model (AADHRR)was built and used for virtual screening of a focussed library of 5900 compounds, which was downloaded from ZINC 15 database. The pharmacophore-based virtual screening filtered out top 1200 hits, based on fitness score. Molecular docking tool like GLIDE was used for structure-based virtual screening in the HTVS (high-throughput virtual screening)mode as it is very fast and less computational power is required. 130 compounds (based on dock score)obtained from HTVS docking were further filtered to 40 hits employing docking in standard precision mode, which is computationally less demanding than docking in extra precision (XP)mode. Finally, best ten hits were identified using docking in XP mode. ZINC14761180 was the best identified hit which was put for molecular dynamics simulations studies and it suggests that ZINC14761180-E6 complex was quite stable for the whole 15ns simulation period. Interestingly, this compound bears 90% similarity with luteolin which has been reported as E6/E7 oncogene inhibitor. QikProp results suggested that identified hits have drug like physico-chemical properties. Present work re-affirms the previous finding that E6AP binding pocket on E6 protein is druggable. These identified hits may act as new leads for inhibition of E6 against cervical cancer.

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