Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation
CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than th...
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doaj-79df135e5b0d4541a4503225996069ec2020-11-25T03:43:51ZengMDPI AGMolecules1420-30492020-10-01254829482910.3390/molecules25204829Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic SimulationSajjad Haider0Assem Barakat1Zaheer Ul-Haq2Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, PakistanDepartment of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi ArabiaDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, PakistanCXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and <i>in-house</i> databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.https://www.mdpi.com/1420-3049/25/20/4829chemokinesmetastasiscancerpharmacophore based virtual screeningCXCR4molecular dynamic simulation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sajjad Haider Assem Barakat Zaheer Ul-Haq |
spellingShingle |
Sajjad Haider Assem Barakat Zaheer Ul-Haq Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation Molecules chemokines metastasis cancer pharmacophore based virtual screening CXCR4 molecular dynamic simulation |
author_facet |
Sajjad Haider Assem Barakat Zaheer Ul-Haq |
author_sort |
Sajjad Haider |
title |
Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation |
title_short |
Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation |
title_full |
Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation |
title_fullStr |
Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation |
title_full_unstemmed |
Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation |
title_sort |
discovery of potential chemical probe as inhibitors of cxcl12 using ligand-based virtual screening and molecular dynamic simulation |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-10-01 |
description |
CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and <i>in-house</i> databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis. |
topic |
chemokines metastasis cancer pharmacophore based virtual screening CXCR4 molecular dynamic simulation |
url |
https://www.mdpi.com/1420-3049/25/20/4829 |
work_keys_str_mv |
AT sajjadhaider discoveryofpotentialchemicalprobeasinhibitorsofcxcl12usingligandbasedvirtualscreeningandmoleculardynamicsimulation AT assembarakat discoveryofpotentialchemicalprobeasinhibitorsofcxcl12usingligandbasedvirtualscreeningandmoleculardynamicsimulation AT zaheerulhaq discoveryofpotentialchemicalprobeasinhibitorsofcxcl12usingligandbasedvirtualscreeningandmoleculardynamicsimulation |
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