Identifying novel sphingosine kinase 1 inhibitors as therapeutics against breast cancer

Khan, Faez Iqbal; Lai, Dakun; Anwer, Razique; Azim, Iffat; Khan, Mohammad Kalim Ahmad

doi:10.1080/14756366.2019.1692828

Cited by 37 publications

(24 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The molecular docking of remdesivir with CTD, Eprotein, Mprotease, Mprotein, NTD, RDRP, and Sprotein was performed using AutoDock Vina ( Trott and Olson, 2010 ). Each of the proteins was individually prepared for docking using standard protocols ( Khan et al, 2020a ; Khan et al, 2020b ; Khan et al, 2021 ). The finest poses of each complex were selected on the foundation of binding energy as well as proper orientation of remdesivir into the active pockets of target proteins ( Schmidt et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

et al. 2021

Self Cite

View full text Add to dashboard Cite

Development of new drugs is a time-taking and expensive process. Comprehensive efforts are being made globally toward the search of therapeutics against SARS-CoV-2. Several drugs such as remdesivir, favipiravir, ritonavir, and lopinavir have been included in the treatment regimen and shown effective results in several cases. Among the existing broad-spectrum antiviral drugs, remdesivir is found to be more effective against SARS-CoV-2. Remdesivir has broad-spectrum antiviral action against many single-stranded RNA viruses including pathogenic SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). In this study, we proposed that remdesivir strongly binds to membrane protein (Mprotein), RNA-dependent RNA polymerase (RDRP), and main protease (Mprotease) of SARS-CoV-2. It might show antiviral activity by inhibiting more than one target. It has been found that remdesivir binds to Mprotease, Mprotein, and RDRP with −7.8, −7.4, and −7.1 kcal/mol, respectively. The structure dynamics study suggested that binding of remdesivir leads to unfolding of RDRP. It has been found that strong binding of remdesivir to Mprotein leads to decrease in structural deviations and gyrations. Additionally, the average solvent-accessible surface area of Mprotein decreases from 127.17 to 112.12 nm2, respectively. Furthermore, the eigenvalues and the trace of the covariance matrix were found to be low in case of Mprotease–remdesivir, Mprotein–remdesivir, and RDRP–remdesivir. Binding of remdesivir to Mprotease, Mprotein, and RDRP reduces the average motions in protein due to its strong binding. The MMPBSA calculations also suggested that remdesivir has strong binding affinity with Mprotein, Mprotease, and RDRP. The detailed analysis suggested that remdesivir has more than one target of SARS-CoV-2.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Here, r i represents the Cartesian coordinate of the i th Cα atom, N represents the number of Cα atoms, and < r i > signifies the time average over all the configurations ( Khan et al, 2020b ; Durrani et al, 2020 ; Hassan et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The solvent accessible surface area (SASA) is explained as the surface area of a protein which forms networks with its solvent molecules [ 23 ]. The average SASA values with respect to backbone for Agp2, PAiRFP1, and PAiRFP2 were found to be 248.60, 252.88, and 250.42 nm 2 , respectively ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

“…The 3D structures were modelled and followed by docking of BV in cis and trans conformations to explore the residual interactions in Pr and Pfr states of Agp2, PAiRFP1, and PAiRFP2. Several 100 ns MD simulations were performed on three targeted bacteriophytochromes to provide some structural information on the basis of root mean square deviation (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), average number of hydrogen bonds, secondary structural analysis, principal component analysis, and Gibbs free energy landscapes [ 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Bacteriophytochrome Agp2 and Its Engineered Photoactivatable NIR Fluorescent Proteins PAiRFP1 and PAiRFP2

et al. 2020

Self Cite

View full text Add to dashboard Cite

Two photoactivatable near infrared fluorescent proteins (NIR FPs) named “PAiRFP1” and “PAiRFP2” are formed by directed molecular evolution from Agp2, a bathy bacteriophytochrome of Agrobacterium tumefaciens C58. There are 15 and 24 amino acid substitutions in the structure of PAiRFP1 and PAiRFP2, respectively. A comprehensive molecular exploration of these bacteriophytochrome photoreceptors (BphPs) are required to understand the structure dynamics. In this study, the NIR fluorescence emission spectra for PAiRFP1 were recorded upon repeated excitation and the fluorescence intensity of PAiRFP1 tends to increase as the irradiation time was prolonged. We also predicted that mutations Q168L, V244F, and A480V in Agp2 will enhance the molecular stability and flexibility. During molecular dynamics (MD) simulations, the average root mean square deviations of Agp2, PAiRFP1, and PAiRFP2 were found to be 0.40, 0.49, and 0.48 nm, respectively. The structure of PAiRFP1 and PAiRFP2 were more deviated than Agp2 from its native conformation and the hydrophobic regions that were buried in PAiRFP1 and PAiRFP2 core exposed to solvent molecules. The eigenvalues and the trace of covariance matrix were found to be high for PAiRFP1 (597.90 nm2) and PAiRFP2 (726.74 nm2) when compared with Agp2 (535.79 nm2). It was also found that PAiRFP1 has more sharp Gibbs free energy global minima than Agp2 and PAiRFP2. This comparative analysis will help to gain deeper understanding on the structural changes during the evolution of photoactivatable NIR FPs. Further work can be carried out by combining PCR-based directed mutagenesis and spectroscopic methods to provide strategies for the rational designing of these PAiRFPs.

show abstract

“…cancer, autoimmune diseases, atherosclerosis, fibrosis) spotlighted SKs as potential targets for drug discovery. 6,7 In this scenario, we focused on the role of SK1/S1P3 axis in the onset of skeletal muscle fibrosis, the hallmark of musculoskeletal myopathies.…”

mentioning

confidence: 99%

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor

Papakyriakou

Cencetti

Puliti

et al. 2020

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator associated to diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis and cancer. Therefore, therapeutic approaches that control S1P production have focused on the development of SK1/2 inhibitors. In this framework, we designed a series of natural monosaccharide-based compounds to enhance anchoring of the known SK1 inhibitor PF-543 at the polar head of the J-shaped substrate-binding channel. Herein, we describe the structure-based design and synthesis of new glycan-containing PF-543 analogues and we demonstrate their efficiency in a TGFβ1-induced pro-fibrotic assay.

show abstract

Identifying novel sphingosine kinase 1 inhibitors as therapeutics against breast cancer

Cited by 37 publications

References 76 publications

Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

Comparative Analysis of Bacteriophytochrome Agp2 and Its Engineered Photoactivatable NIR Fluorescent Proteins PAiRFP1 and PAiRFP2

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor

Contact Info

Product

Resources

About