scholarly journals Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies

2019 ◽  
Vol 20 (4) ◽  
pp. 860 ◽  
Author(s):  
Joao Ramos ◽  
Jayaraman Muthukumaran ◽  
Filipe Freire ◽  
João Paquete-Ferreira ◽  
Ana Otrelo-Cardoso ◽  
...  
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Nucleotide Polymorphisms ◽  
Ligand Interaction ◽  
Zinc Database ◽  
In Silico Studies ◽  
Anti Cancer ◽  
Binding Groove ◽  
The Stability ◽  
Dynamics Simulations

Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2.

Insights into the roles of charged residues in substrate binding and mode of action of mannuronan C-5 epimerase AlgE4

Glycobiology ◽  
2021 ◽  
Author(s):  
Margrethe Gaardløs ◽  
Sergey A Samsonov ◽  
Marit Sletmoen ◽  
Maya Hjørnevik ◽  
Gerd Inger Sætrom ◽  
...  
Keyword(s):  
Optical Tweezers ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
Substrate Binding ◽  
Interdisciplinary Approach ◽  
Product Formation ◽  
Titration Calorimetry ◽  
Binding Groove ◽  
Dynamics Simulations

Abstract Mannuronan C-5 epimerases catalyse the epimerization of monomer residues in the polysaccharide alginate, changing the physical properties of the biopolymer. The enzymes are utilized to tailor alginate to numerous biological functions by alginate-producing organisms. The underlying molecular mechanisms that control the processive movement of the epimerase along the substrate chain is still elusive. To study this, we have used an interdisciplinary approach combining molecular dynamics simulations with experimental methods from mutant studies of AlgE4, where initial epimerase activity and product formation were addressed with NMR spectroscopy, and characteristics of enzyme-substrate interactions were obtained with isothermal titration calorimetry and optical tweezers. Positive charges lining the substrate-binding groove of AlgE4 appear to control the initial binding of poly-mannuronate, and binding also seems to be mediated by both electrostatic and hydrophobic interactions. After the catalytic reaction, negatively charged enzyme residues might facilitate dissociation of alginate from the positive residues, working like electrostatic switches, allowing the substrate to translocate in the binding groove. Molecular simulations show translocation increments of two monosaccharide units before the next productive binding event resulting in MG-block formation, with the epimerase moving with its N-terminus towards the reducing end of the alginate chain. Our results indicate that the charge pair R343-D345 might be directly involved in conformational changes of a loop that can be important for binding and dissociation. The computational and experimental approaches used in this study complement each other, allowing for a better understanding of individual residues’ roles in binding and movement along the alginate chains.

scholarly journals Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

2021 ◽  
Vol 36 (1) ◽  
pp. 1732-1750
Author(s):  
Mohammed M. Alanazi ◽  
Elwan Alaa ◽  
Nawaf A. Alsaif ◽  
Ahmad J. Obaidullah ◽  
Hamad M. Alkahtani ◽  
...  
Keyword(s):  
In Silico ◽  
Design Synthesis ◽  
In Silico Studies ◽  
Anti Cancer

scholarly journals Ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Molbank ◽  
10.3390/m1029 ◽  
2018 ◽  
Vol 2018 (4) ◽  
pp. M1029 ◽  
Author(s):  
Itamar Gonçalves ◽  
Luciano Porto Kagami ◽  
Gustavo Machado das Neves ◽  
Liliana Rockenbach ◽  
Leonardo Davi ◽  
...  
Keyword(s):  
In Silico ◽  
Biginelli Reaction ◽  
Cancer Drugs ◽  
Biological Targets ◽  
In Silico Studies ◽  
Anti Cancer ◽  
Privileged Structure ◽  
Good Potential

The Biginelli reaction is a highly versatile reaction that leads to dihydropyrimidinones/thiones. This scaffold is reported as being a privileged structure due to its ability to interact with biological targets. Synthesis of ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate was achieved through the Biginelli reaction using a functionalized thiourea. In silico studies demonstrated that the compound title showed good potential for interacting with ecto-5’-nucleotidase, which has been considered as a target in designs for anti-cancer drugs.

Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

2014 ◽  
Vol 68 (4) ◽  
Author(s):  
Imran Ali ◽  
Waseem Wani ◽  
Kishwar Saleem ◽  
Ming-Fa Hsieh
Keyword(s):  
Dna Binding ◽  
In Silico ◽  
Binding Constants ◽  
Sodium Hydride ◽  
Nitrogen Atmosphere ◽  
In Silico Studies ◽  
Anti Cancer ◽  
Increasing Demand ◽  
Good Oral Bioavailability ◽  
Mcf 7

AbstractDue to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K b) for the ligand, copper and nickel complexes were 2.09 × 104 M-1, 2.37 × 104 M-1 and 2.11 × 104 M-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.

scholarly journals In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

2020 ◽  
Vol 21 (20) ◽  
pp. 7738
Author(s):  
Joanna Matalińska ◽  
Piotr F. J. Lipiński ◽  
Piotr Kosson ◽  
Katarzyna Kosińska ◽  
Aleksandra Misicka
Keyword(s):  
In Silico ◽  
Molecular Orbital Calculations ◽  
Opioid Use ◽  
Opioid Agonist ◽  
Hybrid Compound ◽  
In Silico Studies ◽  
Neurokinin 1 ◽  
Dynamics Simulations

AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1104
Author(s):  
Rafal Madaj ◽  
Bartlomiej Gostynski ◽  
Roza Pawlowska ◽  
Arkadiusz Chworos
Keyword(s):  
Molecular Dynamics ◽  
Alkaline Phosphatase ◽  
Electrostatic Interactions ◽  
Thermodynamic Integration ◽  
Ligand Docking ◽  
In Silico Studies ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
The Stability ◽  
Dynamics Simulations ◽  
Hydrolysis Of

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.

scholarly journals In-silico analysis of MHC genes in hereditary colorectal cancer shows identical by state SNP sharing affecting HLA-DQB1 binding groove

2016 ◽  
Author(s):  
Mahmoud Koko ◽  
Suleiman Hussein Suleiman ◽  
Mohammed Omar Elsiddieg Abdallah ◽  
Muhallab Saad ◽  
Muntaser Ibrahim
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Cancer Susceptibility ◽  
Human Leukocyte ◽  
Hereditary Colorectal Cancer ◽  
The Cancer Genome Atlas ◽  
Exome Capture ◽  
Nucleotide Polymorphisms ◽  
Mhc Ii ◽  
Binding Groove

Background: The role of Human Leukocyte Antigen (HLA) alleles in colorectal cancer susceptibility, development and progression is the focus of ongoing scrutiny. MHC polymorphisms in a Sudanese family with hereditary colorectal cancer were studied using an in silico approach and the results were verified using The Cancer Genome Atlas (TCGA). In this family study, we tested for sharing of nucleotide polymorphisms identified by whole exome capture in major histocompatibility complex region and carried out in-silico prediction of their effects in tumor and control samples. SNPs were analyzed to highlight identical by state sharing, to identify runs of homozygosity, as well as to predict structural and functional effects using homology modeling, damaging effect predictions, and regulatory changes prediction. Results: MHC II area showed significantly high degree of homozygosity in tumor samples. Non-synonymous SNPs shared identical by state (IBS) between tumor samples were predicted to affect HLA-DQB1 binding groove. A similar haplotype of these SNPs was identified in a TCGA colonic adenocarcinoma tumor sample. No significant regulatory effects (in the form of transcription factor or miRNA binding site variants) were predicted. Conclusions: The results demonstrate IBS SNP sharing of markers affecting HLA-DQB1 binding specificity and probable loss of heterozygosity in MHC II region in colorectal cancer.

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