Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

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Computational design of a thermostable mutant of cocaine esterase via molecular dynamics simulations

Organic & Biomolecular Chemistry ◽

10.1039/c0ob00972e ◽

2011 ◽

Vol 9 (11) ◽

pp. 4138 ◽

Cited By ~ 18

Author(s):

Xiaoqin Huang ◽

Daquan Gao ◽

Chang-Guo Zhan

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Computational Design ◽

Cocaine Esterase ◽

Dynamics Simulations

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Multimodal tubulin binding by the yeast kinesin-8, Kip3, underlies its motility and depolymerization

10.1101/2021.10.12.464151 ◽

2021 ◽

Author(s):

Hugo Arellano-Santoyo ◽

Rogelio A Hernandez-Lopez ◽

Emma Stokasimov ◽

Ray YR Wang ◽

David Pellman ◽

...

Keyword(s):

Molecular Dynamics ◽

Single Molecule ◽

Conformational Changes ◽

Intracellular Transport ◽

Structural Features ◽

Cellular Processes ◽

Tubulin Binding ◽

Dynamics Simulations ◽

Spatiotemporal Control ◽

Unique Ability

The microtubule (MT) cytoskeleton is central to cellular processes including axonal growth, intracellular transport, and cell division, all of which rely on precise spatiotemporal control of MT organization. Kinesin-8s play a key role in regulating MT length by combining highly processive directional motility with MT-end disassembly. However, how kinesin-8 switches between these two apparently opposing activities remains unclear. Here, we define the structural features underlying this molecular switch through cryo-EM analysis of the yeast kinesin-8, Kip3 bound to MTs, and molecular dynamics simulations to approximate the complex of Kip3 with the curved tubulin state found at the MT plus-end. By integrating biochemical and single-molecule biophysical assays, we identified specific intra- and intermolecular interactions that modulate processive motility and MT disassembly. Our findings suggest that Kip3 undergoes conformational changes in response to tubulin curvature that underlie its unique ability to interact differently with the MT lattice than with the MT-end.

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Exploring the binding mechanism of positive allosteric modulators in human metabotropic glutamate receptor 2 using molecular dynamics simulations

Physical Chemistry Chemical Physics ◽

10.1039/d1cp02157e ◽

2021 ◽

Author(s):

Panpan Wang ◽

Xiaonan Gao ◽

Ke Zhang ◽

Qinglan Pei ◽

Xiaobo Xu ◽

...

Keyword(s):

Molecular Dynamics ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Binding Mode ◽

Allosteric Modulators ◽

Binding Mechanism ◽

Metabotropic Glutamate ◽

High Affinity ◽

Dynamics Simulations ◽

High Electronegativity

Based on the binding mode and electrostatics, the features of high affinity PAMs were the reduced hydrophobicity with low electronegativity of R1, increased hydrophobicity with low electronegativity of R2 and with high electronegativity of linker.

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Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2008.10.039 ◽

2008 ◽

Vol 16 (23) ◽

pp. 9957-9974 ◽

Cited By ~ 64

Author(s):

Serdar Durdagi ◽

Thomas Mavromoustakos ◽

Nikos Chronakis ◽

Manthos G. Papadopoulos

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Computational Design ◽

3D Qsar ◽

Binding Interactions ◽

Dynamics Simulations ◽

Hiv 1

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Computational Design of Thiourea-based Cyclophane Sensors for Small Anions

Australian Journal of Chemistry ◽

10.1071/ch11389 ◽

2012 ◽

Vol 65 (3) ◽

pp. 303 ◽

Cited By ~ 4

Author(s):

Huifang Xie ◽

Ming Wah Wong

Keyword(s):

Molecular Dynamics ◽

Binding Affinity ◽

Density Functional ◽

Computational Design ◽

Binding Pocket ◽

Solvent Medium ◽

Guest Binding ◽

Molecular Dynamics Calculations ◽

Anion Complexes ◽

Dynamics Simulations

The host–guest binding properties of a tri-thiourea cyclophane receptor (1) with several common anions have been investigated using density functional theory (DFT) and molecular dynamics calculations. Receptor 1 is predicted to be an effective receptor for binding small halogen and Y-shaped (NO3– and AcO–) anions in the gas phase, cyclohexane and chloroform. The calculated order of anion binding affinity for the receptor 1 in chloroform is F– > Cl– > AcO– > NO3– >Br– > H2PO4– > HSO4–. The binding free energies are strongly influenced by a dielectric solvent medium. The structures of the receptor–anion complexes are characterized by multiple (typically 6) hydrogen bonds in all cases. The overall binding affinity of various anions is determined by the basicity of anion, size and shape of the binding site, and solvent medium. Explicit chloroform solvent molecular dynamics simulations of selected receptor–anion complexes reveal that the anions are strongly bound within the binding pocket via hydrogen-bonding interactions to all the receptor protons throughout the simulation. A sulfur analogue of receptor 1 (2), with a larger central cavity, is shown to be a more effective sensor than 1 for small anions. Two different approaches to develop the thiourea-based cyclophane receptor into a chromogenic sensor were examined.

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Computational design of ACE2-based short peptide inhibitors of SARS-CoV-2

10.26434/chemrxiv.12061734.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Yanxiao Han ◽

Petr Kral

Keyword(s):

Molecular Dynamics ◽

Computational Design ◽

Peptide Inhibitors ◽

Converting Enzyme ◽

Protease Domain ◽

Alpha Helices ◽

Angiotensin Converting Enzyme 2 ◽

Short Peptide ◽

Binding Domains ◽

Dynamics Simulations

<div>Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are formed by two sequential self-supporting alpha-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which binds to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2, determined by their sequences and conformations. The proposed peptide inhibitors could provide simple therapeutics against the COVID-19 disease.</div>

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