Discovery of novel sphingosine kinase 1 inhibitorsvia structure-based hierarchical virtual screening

MedChemComm ◽  
2015 ◽  
Vol 6 (3) ◽  
pp. 413-417 ◽  
Author(s):  
Xiaojian Wang ◽  
Chenbin Sun ◽  
Liang Fang ◽  
Dali Yin
Keyword(s):  
Virtual Screening ◽  
Sphingosine Kinase ◽  
Md Simulations ◽  
Binding Pocket ◽  
Binding Mode ◽  
Positive Control ◽  
Biological Evaluation ◽  
U937 Cells ◽  
Sphingosine Kinase 1 ◽  
Inhibitory Activities

Hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. 25 compounds were selected for biological evaluation. Compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities and anti-proliferative effects on U937 cells to the positive control N,N-dimethylsphingosine (DMS) 1. Further molecule dynamic (MD) simulations revealed the binding mode between SphK1 and 25.

scholarly journals Identification of Novel Type Three Secretion System (T3SS) Inhibitors by Computational Methods and Anti-Salmonella Evaluations

2021 ◽  
Vol 12 ◽  
Author(s):  
Yonghui Wang ◽  
Meihui Hou ◽  
Zhaodong Kan ◽  
Guanghui Zhang ◽  
Yunxia Li ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Development ◽  
Computational Methods ◽  
Type Iii Secretion ◽  
Positive Control ◽  
Biological Evaluation ◽  
Secretion System ◽  
Type Three Secretion System ◽  
Comparable Activity ◽  
Type Three Secretion

Three type III secretion system (T3SS) inhibitors (compounds 5, 19, and 32) were identified by virtual screening and biological evaluation. These three compounds were evaluated against a panel of Salmonella species strains including S. enteritidis, S. typhi, S. typhimurium, S. paratyphi, and S. abortus equi, and their minimum inhibitory concentrations ranged from 1 to 53 μg/ml. Especially, these compounds showed comparable activity as the of the positive control gatifloxacin towards S. abortus equi. The present results suggest that these new T3SS inhibitors could be used as a potential lead molecule for drug development of anti-Salmonella.

scholarly journals Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

Molecules ◽  
2020 ◽  
Vol 25 (1) ◽  
pp. 237 ◽  
Author(s):  
Chunqiong Li ◽  
Xuewen Zhang ◽  
Na Zhang ◽  
Yue Zhou ◽  
Guohui Sun ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Interaction Mechanism ◽  
Pharmacophore Model ◽  
Binding Pocket ◽  
Biological Evaluation ◽  
Atp Binding ◽  
Allosteric Site ◽  
Allosteric Inhibitors ◽  
Competitive Inhibitors ◽  
Reduced Toxicity

Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

Identification of New Hsp90 Inhibitors: Structure Based Virtual Screening, Molecular Dynamic Simulation, Synthesis and Biological Evaluation

2021 ◽  
Vol 21 ◽  
Author(s):  
Maryam Abbasi ◽  
Massoud Amanlou ◽  
Mahmoud Aghaei ◽  
Farshid Hassanzadeh ◽  
Hojjat Sadeghi-Aliabadi
Keyword(s):  
Virtual Screening ◽  
Molecular Dynamic Simulation ◽  
Molecular Dynamic ◽  
Dynamic Simulation ◽  
Md Simulations ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Hsp70 Expression ◽  
Hsp90 Inhibitors ◽  
Screening Study

Background: Heat shock protein90 (Hsp90) is overexpressed in tumor cells, thus the inhibition of the Hsp90 ATPase activity would be a meaningfully an effective strategy in cancer therapy. Objective: The present work was aimed at four steps: designing new Hsp90 inhibitors as anti-cancer by a virtual screening study; synthesize designed compounds; biological evaluation of them and finally molecular dynamic (MD) simulations of best compounds. Methods: A virtual screening study was performed on a library (100 compounds) of the ZINC database with benzimidazole scaffold; then an extracted compound and two derivatives were synthesized. The anti-proliferative and ATPase inhibitory activities of these compounds were evaluated by MTT and ATPase inhibition assays, respectively. The western blot analysis was performed to the evaluation of the expression level of Hsp70 and Her2 proteins. Finally, 200 ns molecular dynamic simulation was carried out to confirm stability the strongest synthesized compound in Hsp90 active site. Results: ZINC00173501 compound with an aminobenzimidazole scaffold was chosen by the virtual screening study. ZINC00173501 compound and two of its derivatives were synthesized. ATPase inhibitory activity of three synthesized compounds shown that ZINC00173501 compound was the most potent inhibitor (IC50= 8.6 μM) with the anti-proliferative activity 14.41 μM, 19.07 μM and more than 100 μM against MCF-7, HeLa and HUVEC cell lines, respectively. The high level of Hsp70 expression and low level of Her2 expression confirmed ZINC00173501 as an Hsp90 inhibitor. Finally, molecular dynamics simulation showed that ZINC00173501 was stable in Hsp90 active cite during 200 ns simulation. Conclusion: The biological evaluation results show that 2-aminobenzimidazole scaffold could be suggested as a lead for inhibition of Hsp90.

scholarly journals Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

2018 ◽  
Vol 172 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Heba Alshaker ◽  
Shyam Srivats ◽  
Danielle Monteil ◽  
Qi Wang ◽  
Caroline M. R. Low ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Biological Evaluation ◽  
Sphingosine Kinase 1

scholarly journals Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1

2020 ◽  
Vol 13 (6) ◽  
pp. 118
Author(s):  
Sonam Roy ◽  
Amarjyoti Das Mahapatra ◽  
Taj Mohammad ◽  
Preeti Gupta ◽  
Mohamed F. Alajmi ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
Cancer Therapeutics ◽  
Sphingosine Kinase ◽  
Binding Pocket ◽  
Van Der Waals Interactions ◽  
Titration Calorimetry ◽  
Sphingosine Kinase 1

Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation.

scholarly journals In Silico Studies, Synthesis and Biological Evaluation of 4,5-Dehydrospisulosine Butyrate Ceramides as Potential Sphingosine Kinase I Inhibitors

2021 ◽  
Author(s):  
Parleen Kaur ◽  
Sonia Sharma ◽  
Vinay Randhawa ◽  
Navneet Agnihotri ◽  
Ramandeep Kaur ◽  
...  
Keyword(s):  
Evaluation Studies ◽  
Docking Simulation ◽  
Sphingosine Kinase ◽  
Biological Evaluation ◽  
High Yield ◽  
Binding Affinities ◽  
Sphingosine Kinase 1 ◽  
Molecular Docking Simulation ◽  
In Silico Studies ◽  
Synthesis And Biological Evaluation

Abstract In the present work, synthesis of 4,5-dehydrospiulosine and its chain analogues (1-3) as potential Sphingosine Kinase I inhibitors has been achieved via the diasteroselective Grignard reaction, stereoselective cross metathesis reaction followed by N-acylation with p-nitrophenyl butyrate to give the corresponding butyrate ceramides (4-6). All compounds were obtained in high yield and purity followed by molecular docking simulation studies using AutoDock which indicated their varying binding affinities with Sphingosine Kinase 1 protein was done. Further, the biological evaluation studies, as potential anti-prostate cancer agents by inhibiting the sphingosine kinase 1 protien of all synthesized compounds (1-6) on PC-3 cell lines by SRB method was done. Compound N-((2S,3S,E)-3 hydroxyheptadec-4-en-2-yl) butyramide (4) exhibited remarkable cytotoxicity with an IC50 value of 6.06 µM.

scholarly journals A second PI(4,5)P2 binding site determines PI(4,5)P2 sensitivity of the tubby domain

2020 ◽  
Author(s):  
Veronika Thallmair ◽  
Lea Schultz ◽  
Siewert J. Marrink ◽  
Dominik Oliver ◽  
Sebastian Thallmair
Keyword(s):  
Binding Site ◽  
Md Simulations ◽  
Binding Pocket ◽  
Binding Mode ◽  
Phosphatidyl Serine ◽  
Coarse Grained ◽  
Membrane Association ◽  
Membrane Interface ◽  
Binding Properties ◽  
Protein Membrane

ABSTRACTPhosphosinositides (PIs) are lipid signaling molecules that operate by recruiting proteins to cellular membranes via PI recognition domains. Such domains are also used widely as fluorescence-coupled biosensors for cellular PIs. For PI(4,5)P2, the dominant PI of the plasma membrane (PM), only two recognition domains have been characterized in detail and used as sensors. One of them, the tubby domain, which is conserved in the tubby-like protein (TULP) family, is essential for targeting proteins into cilia in a process involving reversible membrane association. However, the PI(4,5)P2 binding properties of tubby domains have remained enigmatic.Here we used coarse-grained molecular dynamics (MD) simulations to explore PI(4,5)P2 binding by the prototypic tubby domain (tubbyCT). While the MD simulations showed a comparatively low PI(4,5)P2 affinity of the previously described canonical binding site, they unexpectedly revealed an adjacent second binding site, consisting of a conserved cationic cluster at the protein-membrane interface. Population of this second site dramatically increased membrane association of tubbyCT. Although less specific than the canonical binding pocket, this second site preferred binding of PI(4,5)P2 over PI(4)P and phosphatidyl serine. Mutations in this site impaired PI(4,5)P2-dependent PM localization in living cells and PI(4,5)P2 interaction in silico.Thus, the second binding site essentially contributes to the effective affinity and hence PM association of the tubby domain. The two-ligand binding mode may serve to sharpen the membrane association-dissociation cycle of TULPs that underlies delivery of ciliary cargo.

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