The bulky side chain of antillatoxin is important for potent toxicity: rational design of photoresponsive cytotoxins based on SAR studies

2013 ◽  
Vol 49 (73) ◽  
pp. 8024 ◽  
Author(s):  
Ken Okura ◽  
Shigeru Matsuoka ◽  
Masayuki Inoue
Keyword(s):  
Rational Design ◽  
Side Chain ◽  
Sar Studies ◽  
Bulky Side Chain

Redesign of (R)-Omega-Transaminase and Its Application for Synthesizing Amino Acids with Bulky Side Chain

2021 ◽  
Author(s):  
Dong-Xu Jia ◽  
Chen Peng ◽  
Jun-Liang Li ◽  
Fan Wang ◽  
Zhi-Qiang Liu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Side Chain ◽  
Bulky Side Chain

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

scholarly journals The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

2000 ◽  
Vol 47 (1) ◽  
pp. 47-57 ◽  
Author(s):  
J Mazerski ◽  
I Antonini ◽  
S Martelli
Keyword(s):  
Molecular Dynamics ◽  
Rational Design ◽  
Md Simulations ◽  
Ring System ◽  
Side Chain ◽  
Side Chains ◽  
Intercalation Complex ◽  
Highly Active ◽  
Simulation Techniques ◽  
Dynamics Simulations

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

Rational Design of an Anticalin-Type Sugar-Binding Protein Using a Genetically Encoded Boronate Side Chain

2017 ◽  
Vol 6 (12) ◽  
pp. 2241-2247 ◽  
Author(s):  
Selvakumar Edwardraja ◽  
Andreas Eichinger ◽  
Ina Theobald ◽  
Carina Andrea Sommer ◽  
Andreas J. Reichert ◽  
...  
Keyword(s):  
Rational Design ◽  
Binding Protein ◽  
Side Chain ◽  
Sugar Binding

scholarly journals Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Vasantha Rao Dola ◽  
Awakash Soni ◽  
Pooja Agarwal ◽  
Hafsa Ahmad ◽  
Kanumuri Siva Rama Raju ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid State ◽  
Side Chain ◽  
Detailed Structure ◽  
Preclinical Development ◽  
Malaria Parasites ◽  
Sar Studies ◽  
Structure Activity

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

Mechanical and dielectric properties of bulky side chain poly(methacrylates). Analysis of the low frequency phenomena. 1: Poly(5-indanyl methacrylate)

1997 ◽  
Vol 37 (5) ◽  
pp. 882-887 ◽  
Author(s):  
Ricardo Diaz Calleja ◽  
Catherine Jaime's ◽  
M. J. Sanchis-Sanchez ◽  
Francisco Martinez-Piña ◽  
Ligia Gargallo ◽  
...  
Keyword(s):  
Dielectric Properties ◽  
Low Frequency ◽  
Side Chain ◽  
Bulky Side Chain

scholarly journals Structure-Activity Relationships in the Design of Mitochondria-Targeted Peptide Therapeutics

2021 ◽  
Author(s):  
Wayne Mitchell ◽  
Jeffrey Tamucci ◽  
Emery Ng ◽  
Shaoyi Liu ◽  
Hazel H Szeto ◽  
...  
Keyword(s):  
Rational Design ◽  
Membrane Surface ◽  
Membrane Properties ◽  
Side Chain ◽  
Aromatic Side Chain ◽  
Binding Behavior ◽  
Membrane Electrostatics ◽  
Peptide Analogs ◽  
Structure Activity ◽  
Chain Composition

Mitochondria play a central role in metabolic homeostasis; hence, dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Mitochondria-targeted tetrapeptides with alternating cationic and aromatic residues, such as SS-31 (Elamipretide), show promise as therapeutic compounds. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs that differed with respect to aromatic side chain composition and sequence register, benchmarked against SS-31. Using NMR and molecular dynamics approaches, we obtained the first structural models for this class of compounds, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, the analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. All peptide analogs preserved survival and energy metabolism more effectively than SS-31 in cell stress models. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register strongly influence the activity of these mitochondria-targeted peptides. Furthermore, this work helps provide a framework for the rational design of next-generation therapeutics with enhanced potency.

scholarly journals Insights into the mechanisms of LOV domain color tuning from a set of high-resolution X-ray structures

2021 ◽  
Author(s):  
Alina Remeeva ◽  
Vera V. Nazarenko ◽  
Kirill Kovalev ◽  
Ivan Goncharov ◽  
Anna Yudenko ◽  
...  
Keyword(s):  
Amino Acid ◽  
High Resolution ◽  
Rational Design ◽  
Fluorescent Protein ◽  
Fluorescent Proteins ◽  
Side Chain ◽  
Lov Domain ◽  
Charged Amino Acids ◽  
C Terminus ◽  
Maximal Shift

AbstractLight-oxygen-voltage (LOV) domains are widespread photosensory modules that can be used in fluorescence microscopy, optogenetics and controlled production of reactive oxygen species. All of the currently known LOV domains have absorption maxima in the range of ∼440 to ∼450 nm, and it is not clear whether they can be shifted significantly using mutations. Here, we have generated a panel of LOV domain variants by mutating the key chromophore-proximal glutamine amino acid of a thermostable flavin based fluorescent protein CagFbFP (Gln148) to asparagine, aspartate, glutamate, histidine, lysine and arginine. Absorption spectra of all of the mutants are blue-shifted, with the maximal shift of 8 nm observed for the Q148H variant. While CagFbFP and its Q148N/D/E variants are not sensitive to pH, Q148H/K/R reveal a moderate red shift induced by acidic pH. To gain further insight, we determined high resolution crystal structures of all of the mutants studied at the resolutions from 1.07 Å for Q148D to 1.63 Å for Q148R. Whereas in some of the variants, the amino acid 148 remains in the vicinity of the flavin, in Q148K, Q148R and partially Q148D, the C-terminus of the protein unlatches and the side chain of the residue 148 is reoriented away from the chromophore. Our results explain the absence of color shifts from replacing Gln148 with charged amino acids and pave the way for rational design of color-shifted flavin based fluorescent proteins.

scholarly journals A conserved evolutionary mechanism permits Δ9 desaturation of very-long-chain fatty acyl lipids

2020 ◽  
Vol 295 (32) ◽  
pp. 11337-11345
Author(s):  
Yuanheng Cai ◽  
Xiao-Hong Yu ◽  
Jin Chai ◽  
Chang-Jun Liu ◽  
John Shanklin
Keyword(s):  
Binding Pocket ◽  
Fatty Acyl ◽  
Single Amino Acid ◽  
Side Chain ◽  
Surface Residue ◽  
Binding Cavity ◽  
Acyl Lipids ◽  
Acyl Chains ◽  
Long Chain ◽  
Bulky Side Chain

Δ9 fatty acyl desaturases introduce a cis–double bond between C9 and C10 of saturated fatty acyl chains. From the crystal structure of the mouse stearoyl-CoA desaturase (mSCD1) it was proposed that Tyr-104, a surface residue located at the distal end of the fatty acyl binding pocket plays a key role in specifying 18C selectivity. We created mSCD1-Y104G to test the hypothesis that eliminating this bulky side chain would create an opening and permit the substrate's methyl end to protrude through the enzyme into the lipid bilayer, facilitating the desaturation of very-long-chain (VLC) substrates. Consistent with this hypothesis, Y104G acquired the ability to desaturate 24C and 26C acyl-CoAs while maintaining its Δ9-regioselectivity. We also investigated two distantly related very-long-chain fatty acyl (VLCFA) desaturases from Arabidopsis, ADS1.2 and ADS1.4, which have Ala and Gly, respectively, in place of the gatekeeping Tyr found in mSCD1. Substitution of Tyr for Ala and Gly in ADS1.2 and ADS1.4, respectively, blocked their ability to desaturate VLCFAs. Further, we identified a pair of fungal desaturase homologs which contained either an Ile or a Gly at this location and showed that only the Gly-containing desaturase was capable of very-long-chain desaturation. The conserved desaturase architecture wherein a surface residue with a single bulky side chain forms the end of the substrate binding cavity predisposes them to single amino acid substitutions that enable a switch between long- and very-long-chain selectivity. The data presented here show that such changes have independently occurred multiple times during evolution.

New bulky side chain substituted benzodithiophene based 2D-conjugated polymers for optoelectronic applications

2016 ◽  
Vol 73 (9) ◽  
pp. 2567-2581 ◽  
Author(s):  
Kakaraparthi Kranthiraja ◽  
Sang Ho Park ◽  
Woosum Cho ◽  
Won-Tae Park ◽  
Yong-Young Noh ◽  
...  
Keyword(s):  
Conjugated Polymers ◽  
Side Chain ◽  
Optoelectronic Applications ◽  
Bulky Side Chain
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