Abstract
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.
Highlights
Breast cancer is the most commonly diagnosed cancer among women worldwide
molecular dynamics (MD) simulations were performed on Sphingosine kinase 1 (SphK1), SphK1–PF-543, SphK1–ZINC06823429, SphK1–ZINC95421070, and SphK1–ZINC 95421501 at 300 K at the molecular mechanics (MM) level executed by GROMACS 5.1.254 utilising the GROMOS96 43a1 force-field
The selected compounds were subjected to ADMET screening which includes in silico prediction of human intestinal absorption (HIA), and blood brain barrier (BBB) parameters of pharmacokinetics
Summary
Breast cancer is the most commonly diagnosed cancer among women worldwide. A majority of patients diagnosed with breast cancer go on to develop symptoms of post-traumatic stress disorder, and in most of these cases the symptoms persist for at least a year[1]. The breast cancer mortality rates have been declined in the past few years owing to early diagnosis and advancement in treatments[5] The present medication such as endocrine therapy for the different subtypes of breast cancer is utilised for the treatment and prevention of oestrogen-receptor-positive (ERþ) breast carcinoma[6]. The S1P regulates various biological processes such as cell development, anti-apoptosis, intrusion, angiogenesis, and expansion after attaching to five selective G protein-coupled receptor (GPCRs) located on the plasma membrane (S1P1-5). This in turn stimulates ERK1/2 prompting downstream signalling that is a crucial step for metastasis of breast cancer[14]. This study may provide valuable insight leading to improved treatment of patients with breast cancer
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