TY - JOUR
T1 - Identifying novel sphingosine kinase 1 inhibitors as therapeutics against breast cancer
AU - Khan, Faez Iqbal
AU - Lai, Dakun
AU - Anwer, Razique
AU - Azim, Iffat
AU - Khan, Mohd Kalim Ahmad
N1 - Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (ΔG) of three screened compounds namely ZINC06823429 (–11.36 kcal/mol), ZINC95421501 (–11.29 kcal/mol), and ZINC95421070 (–11.26 kcal/mol) exhibited stronger than standard drug PF-543 (–9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.
AB - Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (ΔG) of three screened compounds namely ZINC06823429 (–11.36 kcal/mol), ZINC95421501 (–11.29 kcal/mol), and ZINC95421070 (–11.26 kcal/mol) exhibited stronger than standard drug PF-543 (–9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.
KW - MD simulation
KW - MMPBSA calculations
KW - SphK1
KW - breast cancer
KW - molecular docking
UR - http://www.scopus.com/inward/record.url?scp=85075467521&partnerID=8YFLogxK
U2 - 10.1080/14756366.2019.1692828
DO - 10.1080/14756366.2019.1692828
M3 - Article
C2 - 31752564
AN - SCOPUS:85075467521
SN - 1475-6366
VL - 35
SP - 172
EP - 186
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 1
ER -
