scholarly journals Lectins-glycoconjugates interactions: Experimental and computational docking studies of the binding and agglutination of eight different lectins in a comparative manner

2020 ◽  
Author(s):  
Amit Kumar ◽  
Vijaya Kumar Hinge ◽  
Ashapogu Venugopal ◽  
Siva Kumar Nadimpalli ◽  
Chebrolu Pulla Rao
Keyword(s):  
Conformational Changes ◽  
Hydrophobic Interactions ◽  
Cd Spectroscopy ◽  
Docking Studies ◽  
Model Systems ◽  
Computational Docking ◽  
Differential Recognition ◽  
Polar Interactions ◽  
Lectin Specificity ◽  
Comparative Manner

ABSTRACTAltering the lectin properties by chemically synthesized glycoconjugates is important in glycobiology. A series of eight plant lectins with varying carbohydrate specificity were chosen as model systems to study the binding by synthetic glycoconjugates. One of our earlier paper 1 deals with the binding of glycoconjugates by jacalin. Further to this, we have now extended the studies to several other lectins having specificities towards glucose/mannose, galactose and lactose, and the results are reported in this paper on a comparative manner. The binding aspects were established by hemagglutination and fluorescence spectroscopy, and the conformational changes by CD spectroscopy. Out of the fourteen glycoconjugates used in the present study, a galactosyl-naphthyl derivative, 1c turns out to be most effective towards galactose-specific lectin in agglutination inhibition, fluorescence quenching by inducing considerable conformational changes. Similarly, mannosyl-naphthyl derivative, 3c turns out to be most effective in inhibiting the agglutination of Glc/Man specific lectins. Present study demonstrates differential recognition of conjugates towards lectins. The results also supported the existence of a correlation between the glycoconjugate and lectin specificity at the carbohydrate recognition domain (CRD). The glycoconjugate that inhibits the agglutination binds in the CRD via polar interactions as well as by nonpolar/hydrophobic interactions arising from the aromatic moiety of the conjugate, whereas, the non-inhibiting conjugates bind primarily via hydrophobic interactions. The specific and selective binding of the glycoconjugates by these lectins were proven by the docking studies. Thus, the present study has contributed immensely towards understanding the molecular interactions present between the lectins and small molecules that will eventually help better drug design where the presence of hydrophoibic moieties would play important role.

Inhibitory as well as disaggregation potential of selected hydroxy benzoic phytochemicals on hen egg white lysozyme amyloidogenesis

2020 ◽  
Vol 17 ◽  
Author(s):  
Nandini Sarkar ◽  
Vidyalatha Kolli ◽  
Taraka Prabhu MP ◽  
Arbin Basak ◽  
Hitesh Mandal
Keyword(s):  
Conformational Changes ◽  
Vanillic Acid ◽  
Egg White ◽  
Cd Spectroscopy ◽  
Docking Studies ◽  
Amyloid Formation ◽  
Hen Egg White Lysozyme ◽  
Egg White Lysozyme ◽  
Hen Egg White ◽  
Hen Egg

Background: Amyloids are a class of ordered protein aggregates which have been implicated in the onset of several degenerative diseases such as Alzheimer's disease, Parkinson's disease, Type II diabetes and so on. Despite extensive research, the exact mechanism and the driving factors for the amyloidogenesis process remain elusive. Identifying molecules which can effectively inhibit and/or disaggregate the fibrils may be one effective therapeutic strategy against amyloidosis Objectives: In the current study, few hydroxy-benzoic phytochemicals were selected to study their effects on formation as well as disaggregation of hen egg white lysozyme (HEWL) amyloids, namely gallic acid, syringic acid, vanillic acid and iso-vanillic acid. Method: Amyloidogenesis was monitored using methods like the thioflavin T assay, field emission scanning electron mi-croscopy (FESEM) and dynamic light scattering (DLS) studies. Further protein conformational changes were monitored us-ing methods like 8-Anilino-naphthalene-1-sulfonate (ANS) fluorescence, circular dichroism (CD) spectroscopy and guani-dine hydrochloride mediated stability studies. Computational approach was also employed to get an insight on the interac-tion(s) between the selected compounds and HEWL using docking studies Result: The selected compounds exhibited significant inhibitory as well as disaggregation effects on HEWL amyloids. In-teraction with the phytochemicals was also associated with considerable conformational changes in HEWL. Docking studies show role of hydrogen bonding between HEWL and the phytochemicals. Conclusion: Thus the current study throws light on the key factors that drive amyloid formation and hence will be helpful for development of effective therapeutics against amyloidosis.

Selection of oxypeucedanin as a potential antagonist from molecular docking analysis of HSP90

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Joshua Oluwasegun Bamidele ◽  
George Oche Ambrose ◽  
Oluwaseun Suleiman Alakanse
Keyword(s):  
Molecular Docking ◽  
Liver Toxicity ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Docking Analysis ◽  
Computational Docking ◽  
Drug Candidates ◽  
Expression Rate ◽  
Client Proteins

AbstractHSP90 is observed as one of the copious molecular chaperones that play a key role in mediating appropriate folding, maturation, and firmness of many client proteins in cells. The expression rate of HSP90 in cancer cells is at a level of 2- to 10-fold higher than the 1- to 2-fold of its unstressed and healthy ones. To combat this, several inhibitors to HSP90 protein have been studied (such as geldanamycin and its derivative 17-AAG and 17-DMAG) and have shown some primary side effects including plague, nausea, vomiting, and liver toxicity, hence the search for the best-in-class inhibitor for this protein through in silico. This study is aimed at analyzing the inhibitory potency of oxypeucedanin-a furocoumarin derivations, which have been reported to have antipoliferative activity in human prostrate carcinoma DN145 cells, and three other drug candidates retrieved from the literature via computational docking studies. The results showed oxypeucedanin as the compound with the highest binding energy of −9.2 kcal/mol. The molecular docking study was carried out using PyRx, Auto Dock Vina option, and the target was validated to confirm the proper target and the docking procedure employed for this study.

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 Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

2021 ◽  
Vol 14 (2) ◽  
pp. 169
Author(s):  
Gloria Ana ◽  
Patrick M. Kelly ◽  
Azizah M. Malebari ◽  
Sara Noorani ◽  
Seema M. Nathwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Mitotic Catastrophe ◽  
Phase Cell ◽  
Computational Docking ◽  
Er Positive ◽  
Mcf 7

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

Structure, stability and folding of the α-helix

2001 ◽  
Vol 68 ◽  
pp. 95-110 ◽  
Author(s):  
Andrew J. Doig ◽  
Charles D. Andrew ◽  
Duncan A. E. Cochran ◽  
Eleri Hughes ◽  
Simon Penel ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Hydrophobic Interactions ◽  
Data Bank ◽  
Site Directed Mutagenesis ◽  
Model Systems ◽  
Side Chain ◽  
Structure Stability ◽  
Helical Peptides ◽  
Vast Number ◽  
Α Helix

Pauling first described the α-helix nearly 50 years ago, yet new features of its structure continue to be discovered, using peptide model systems, site-directed mutagenesis, advances in theory, the expansion of the Protein Data Bank and new experimental techniques. Helical peptides in solution form a vast number of structures, including fully helical, fully coiled and partly helical. To interpret peptide results quantitatively it is essential to use a helix/coil model that includes the stabilities of all these conformations. Our models now include terms for helix interiors, capping, side-chain interactions, N-termini and 310-helices. The first three amino acids in a helix (N1, N2 and N3) and the preceding N-cap are unique, as their amide NH groups do not participate in backbone hydrogen bonding. We surveyed their structures in proteins and measured their amino acid preferences. The results are predominantly rationalized by hydrogen bonding to the free NH groups. Stabilizing side-chain-side-chain energies, including hydrophobic interactions, hydrogen bonding and polar/non-polar interactions, were measured accurately in helical peptides. Helices in proteins show a preference for having approximately an integral number of turns so that their N- and C-caps lie on the same side. There are also strong periodic trends in the likelihood of terminating a helix with a Schellman or αL C-cap motif. The kinetics of α-helix folding have been studied with stopped-flow deep ultraviolet circular dichroism using synchrotron radiation as the light source; this gives a far superior signal-to-noise ratio than a conventional instrument. We find that poly(Glu), poly(Lys) and alanine-based peptides fold in milliseconds, with longer peptides showing a transient overshoot in helix content.

Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity

2014 ◽  
Vol 112 (07) ◽  
pp. 53-64 ◽  
Author(s):  
Sven Brandt ◽  
Krystin Krauel ◽  
Kay E. Gottschalk ◽  
Thomas Renné ◽  
Christiane A. Helm ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Cd Spectroscopy ◽  
Platelet Factor 4 ◽  
Drug Induced ◽  
Platelet Factor ◽  
Preclinical Drug Development ◽  
Varying Length ◽  
Endogenous Proteins

SummaryHeparin-induced thrombocytopenia (HIT) is the most frequent drug-induced immune reaction affecting blood cells. Its antigen is formed when the chemokine platelet factor 4 (PF4) complexes with polyanions. By assessing polyanions of varying length and degree of sulfation using immunoassay and circular dichroism (CD)-spectroscopy, we show that PF4 structural changes resulting in antiparallel β-sheet content >30% make PF4/polyanion complexes antigenic. Further, we found that polyphosphates (polyP-55) induce antigenic changes on PF4, whereas fondaparinux does not. We provide a model suggesting that conformational changes exposing antigens on PF4/polyanion complexes occur in the hairpin involving AA 32–38, which form together with C-terminal AA (66–70) of the adjacent PF4 monomer a continuous patch on the PF4 tetramer surface, explaining why only tetrameric PF4 molecules express “HIT antigens”. The correlation of antibody binding in immunoassays with PF4 structural changes provides the intriguing possibility that CD-spectroscopy could become the first antibody-independent, in vitro method to predict potential immunogenicity of drugs. CD-spectroscopy could identify compounds during preclinical drug development that induce PF4 structural changes correlated with antigenicity. The clinical relevance can then be specifically addressed during clinical trials. Whether these findings can be transferred to other endogenous proteins requires further studies.

scholarly journals Conformational variability in proteins bound to single-stranded DNA: a new benchmark for new docking perspectives

2021 ◽  
Author(s):  
Dominique MIAS-LUCQUIN ◽  
Isaure Chauvot de Beauchêne
Keyword(s):  
Protein Data Bank ◽  
Conformational Changes ◽  
Molecular Interactions ◽  
Protein Structures ◽  
Data Bank ◽  
Computational Docking ◽  
Ssdna Binding ◽  
Conformational Variability ◽  
High Flexibility ◽  
Docking Benchmark

We explored the Protein Data-Bank (PDB) to collect protein-ssDNA structures and create a multi-conformational docking benchmark including both bound and unbound protein structures. Due to ssDNA high flexibility when not bound, no ssDNA unbound structure is included. For the 143 groups identified as bound-unbound structures of the same protein , we studied the conformational changes in the protein induced by the ssDNA binding. Moreover, based on several bound or unbound protein structures in some groups, we also assessed the intrinsic conformational variability in either bound or unbound conditions, and compared it to the supposedly binding-induced modifications. This benchmark is, to our knowledge, the first attempt made to peruse available structures of protein – ssDNA interactions to such an extent, aiming to improve computational docking tools dedicated to this kind of molecular interactions.

Molten globule state of human placental cystatin (HPC) at low pH conditions and the effects of trifluoroethanol (TFE) and methanol

2006 ◽  
Vol 84 (2) ◽  
pp. 126-134 ◽  
Author(s):  
Fouzia Rashid ◽  
Sandeep Sharma ◽  
M A Baig ◽  
Bilqees Bano
Keyword(s):  
Conformational Changes ◽  
Tertiary Structure ◽  
Molten Globule ◽  
Structural Features ◽  
Cd Spectroscopy ◽  
Native State ◽  
Molten Globule State ◽  
Fluorescence Measurements ◽  
Helical Content ◽  
Human Placental Cystatin

Acid-induced conformational changes were studied in human placental cystatin (HPC) in terms of circular dichroism (CD) spectroscopy, the binding of hydrophobic dye 1-anilinonapthalene-8-sulphonic acid (ANS), and intrinsic fluorescence measurements. Our results show the formation of an acid-induced molten globule state at pH 2.0, with significant secondary and tertiary interactions that resemble the native state, exposed hydrophobic regions and the effects of trifluoroethanol (TFE) and methanol in conversion of the acid-denatured state of HPC to the alcohol-induced state, which is characterized by increased helical content, disrupted tertiary structure, and the absence of hydrophobic clusters. Alcohol-induced formation of α-helical structures at pH 2.0 is evident from the increase in the ellipticity values at 222 nm, with native-like secondary structural features at 40% TFE. The increase in helical content was observed up to 80% TFE concentration. The ability of TFE (40%) to refold acid-denatured HPC to native-state conformation is also supported by intrinsic and ANS fluorescence measurements.Key words: human placental cystatin, molten globule, acid-induced state, trifluoroethanol, methanol, CD spectroscopy, ANS fluorescence, pH, protein folding.

Computational Investigation of Versatile Activity of Piperine

2019 ◽  
pp. 127-139
Author(s):  
Thenmozhi Marudhadurai ◽  
Navabshan Irfan
Keyword(s):  
Docking Study ◽  
Black Pepper ◽  
Docking Studies ◽  
Therapeutic Activity ◽  
Computational Docking ◽  
Target Proteins ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Anti Oxidant ◽  
Inhibition Property

Piperine is known for its versatile therapeutic activity. It has been used for various disease conditions (e.g., cold, cough, etc.). Piperine is an alkaloid found in black pepper. It possesses various pharmacological actions like anti-inflammatory, anti-oxidant, anti-cholinergic, and anti-cancerous. The above-mentioned properties will be studied by selecting target proteins COX-2 protein, angiotensin converting enzyme, acetylcholineesterases, and survivin using computational docking study. This chapter explains the inhibition property of piperine against selected target protein from the results of docking studies. Based on the docking scores and protein-ligand interactions, piperine was found to bind well in the active site of the selected target proteins. It ensures the binding efficacy of piperine against selected target proteins. Docking scores and protein-ligand interactions plays an important role in its therapeutic activity.

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