scholarly journals Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

2021 ◽  
Vol 22 (11) ◽  
pp. 5685
Author(s):  
Héctor Torres-Gómez ◽  
Constantin Daniliuc ◽  
Dirk Schepmann ◽  
Erik Laurini ◽  
Sabrina Pricl ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Membered Ring ◽  
Receptor Protein ◽  
Receptor Ligands ◽  
Hydrophobic Region ◽  
Bond Forming ◽  
Σ1 Receptor ◽  
Bioisosteric Replacement ◽  
Dynamics Simulations ◽  
The Right

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ1 receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the “left” five-membered ring and various amino groups on the “right” side; (2) benzylamino or analogous amino moieties on the “right” side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ1 affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ1 affinity (Ki = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the “left” hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ1 affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ1 affinity of 9a (Ki = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ1 receptor, which result in energetic values correlating well with their different σ1 affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ1 receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ1 receptor-binding pocket, which explains the higher σ1 affinity of the unsubstituted azapropellane 9a.

scholarly journals Exploring aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction: an in silico study

2021 ◽  
Author(s):  
Chiara Luise ◽  
Dina Robaa ◽  
Wolfgang Sippl
Keyword(s):  
Molecular Dynamic ◽  
In Silico ◽  
Binding Pocket ◽  
Binding Mode ◽  
Molecular Dynamic Simulations ◽  
Flexible Docking ◽  
Dynamic Simulations ◽  
Binding Mode Prediction ◽  
Aromatic Cage ◽  
The Right

AbstractSome of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.

scholarly journals Thermal Conductivity of Cage-Like Structures

2011 ◽  
Author(s):  
Mona Zebarjadi ◽  
Keivan Esfarjani ◽  
Gang Chen
Keyword(s):  
Thermal Conductivity ◽  
Atomic Displacement ◽  
Rectangular Lattice ◽  
Local Minima ◽  
Atomic Displacement Parameter ◽  
Band Dispersion ◽  
Dynamics Simulations ◽  
Filler Mass ◽  
The Right ◽  
Double Well Potential

A two dimensional toy model is developed to study thermal transport in cage like structures such a skutterudites and clathrates. The model consists of host atoms on a rectangular lattice with fillers in the center of each rectangle. The thermal conductivity is calculated by using Green-Kubo equilibrium molecular dynamics simulations. It is generally believed that the smaller and the heavier the filler, the lower is the thermal conductivity. We show that the thermal conductivity decreases with atomic displacement parameter while it has local minima versus filler mass. Our study shows that it is very important to include the correct band dispersion to get the right features of the thermal conductivity. We show that by having a double well potential one can further reduce the thermal conductivity.

5D-QSAR for spirocyclic σ1 receptor ligands by Quasar receptor surface modeling

2010 ◽  
Vol 45 (7) ◽  
pp. 3116-3124 ◽  
Author(s):  
Christoph Oberdorf ◽  
Thomas J. Schmidt ◽  
Bernhard Wünsch
Keyword(s):  
Surface Modeling ◽  
Receptor Ligands ◽  
Σ1 Receptor

scholarly journals A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 384 ◽  
Author(s):  
Giuseppe Floresta ◽  
Emanuele Amata ◽  
Carla Barbaraci ◽  
Davide Gentile ◽  
Rita Turnaturi ◽  
...  
Keyword(s):  
Natural Products ◽  
Tumor Cell ◽  
Marine Natural Products ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Receptor Protein ◽  
Receptor Ligands ◽  
Tumor Cell Death ◽  
Targeting Therapy

Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor.

scholarly journals The β-cyclodextrin/benzene complex and its hydrogen bonds – a theoretical study using molecular dynamics, quantum mechanics and COSMO-RS

2013 ◽  
Vol 9 ◽  
pp. 118-134 ◽  
Author(s):  
Jutta Erika Helga Köhler ◽  
Nicole Grczelschak-Mick
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Hydrogen Bonds ◽  
Md Simulations ◽  
Benzene Molecule ◽  
Glucose Unit ◽  
Hand Orientation ◽  
Different Temperatures ◽  
Dynamics Simulations ◽  
The Right

Four highly ordered hydrogen-bonded models of β-cyclodextrin (β-CD) and its inclusion complex with benzene were investigated by three different theoretical methods: classical quantum mechanics (QM) on AM1 and on the BP/TZVP-DISP3 level of approximation, and thirdly by classical molecular dynamics simulations (MD) at different temperatures (120 K and 273 to 300 K). The hydrogen bonds at the larger O2/O3 rim of empty β-CDs prefer the right-hand orientation, e.g., O3-H…O2-H in the same glucose unit and bifurcated towards …O4 and O3 of the next glucose unit on the right side. On AM1 level the complex energy was −2.75 kcal mol−1 when the benzene molecule was located parallel inside the β-CD cavity and −2.46 kcal mol−1 when it was positioned vertically. The AM1 HOMO/LUMO gap of the empty β-CD with about 12 eV is lowered to about 10 eV in the complex, in agreement with data from the literature. AM1 IR spectra displayed a splitting of the O–H frequencies of cyclodextrin upon complex formation. At the BP/TZVP-DISP3 level the parallel and vertical positions from the starting structures converged to a structure where benzene assumes a more oblique position (−20.16 kcal mol−1 and −20.22 kcal mol−1, resp.) as was reported in the literature. The character of the COSMO-RS σ-surface of β-CD was much more hydrophobic on its O6 rim than on its O2/O3 side when all hydrogen bonds were arranged in a concerted mode. This static QM picture of the β-CD/benzene complex at 0 K was extended by MD simulations. At 120 K benzene was mobile but always stayed inside the cavity of β-CD. The trajectories at 273, 280, 290 and 300 K certainly no longer displayed the highly ordered hydrogen bonds of β-CD and benzene occupied many different positions inside the cavity, before it left the β-CD finally at its O2/O3 side.

scholarly journals Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4636 ◽  
Author(s):  
Sabina Podlewska ◽  
Ryszard Bugno ◽  
Lucja Kudla ◽  
Andrzej J. Bojarski ◽  
Ryszard Przewlocki
Keyword(s):  
Molecular Modeling ◽  
G Protein ◽  
Opioid Receptor ◽  
Pearson Correlation ◽  
Interaction Patterns ◽  
Receptor Ligands ◽  
Opioid Receptor Ligands ◽  
Dynamics Simulations

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

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