scholarly journals Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

2020 ◽  
Author(s):  
Daniel Sindhikara ◽  
Michael Wagner ◽  
Paraskevi Gkeka ◽  
Stefan Guessregen ◽  
Garima Tiwari ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cyclic Peptides ◽  
Conformational Stability ◽  
Three Dimensional ◽  
Cell Permeability ◽  
Linear Molecule ◽  
Retrospective Case ◽  
Therapeutic Modalities ◽  
Protein Interfaces ◽  
Starting Point

<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>

scholarly journals Automated Design of Macrocycles for Therapeutic Applications: from Small Molecules to Peptides and Proteins

2020 ◽  
Author(s):  
Daniel Sindhikara ◽  
Michael Wagner ◽  
Paraskevi Gkeka ◽  
Stefan Guessregen ◽  
Garima Tiwari ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cyclic Peptides ◽  
Conformational Stability ◽  
Three Dimensional ◽  
Cell Permeability ◽  
Linear Molecule ◽  
Retrospective Case ◽  
Therapeutic Modalities ◽  
Protein Interfaces ◽  
Starting Point

<div>Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have </div><div>improved affinity, are able to bind to extended protein interfaces and otherwise have favorable </div><div>properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive </div><div>conformation, improve its metabolic stability, cell permeability and in certain cases oral </div><div>bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and </div><div>proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the </div><div>three-dimensional (3D) conformation of the linear molecule in complex with a target protein as </div><div>starting point, this approach identifies attachment points, generates linkers, evaluates the </div><div>conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting </div><div>molecules with respect to their predicted conformational stability and interactions with the target </div><div>protein. As we show here with several prospective and retrospective case studies, this procedure can </div><div>be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.</div><div>The presented approach is an important step towards the enhanced utilization of macrocycles and</div><div>cyclic peptides as attractive therapeutic modalities.</div>

scholarly journals Improvement on Permeability of Cyclic Peptide/Peptidomimetic: Backbone N-Methylation as A Useful Tool

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 311
Author(s):  
Yang Li ◽  
Wang Li ◽  
Zhengshuang Xu
Keyword(s):  
Cyclic Peptides ◽  
Cyclic Peptide ◽  
Three Dimensional ◽  
Conformational Space ◽  
Cell Permeability ◽  
Relative Importance ◽  
Intrinsic Properties ◽  
Surface Areas ◽  
Synthetic Methodologies ◽  
Three Dimensional Configuration

Peptides have a three-dimensional configuration that can adopt particular conformations for binding to proteins, which are well suited to interact with larger contact surface areas on target proteins. However, low cell permeability is a major challenge in the development of peptide-related drugs. In recent years, backbone N-methylation has been a useful tool for manipulating the permeability of cyclic peptides/peptidomimetics. Backbone N-methylation permits the adjustment of molecule’s conformational space. Several pathways are involved in the drug absorption pathway; the relative importance of each N-methylation to total permeation is likely to differ with intrinsic properties of cyclic peptide/peptidomimetic. Recent studies on the permeability of cyclic peptides/peptidomimetics using the backbone N-methylation strategy and synthetic methodologies will be presented in this review.

Backbone-Enabled Peptide Macrocyclization through Late-Stage Palladium-Catalyzed C–H Activation

Synlett ◽  
2019 ◽  
Vol 31 (03) ◽  
pp. 199-204 ◽  
Author(s):  
Zengbing Bai ◽  
Huan Wang
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Late Stage ◽  
Cyclic Peptides ◽  
Medicinal Chemistry ◽  
Materials Science ◽  
Three Dimensional ◽  
Chemical Methods ◽  
New Methods ◽  
Palladium Catalyzed

Peptide macrocycles are widely used in fields ranging from medicinal chemistry to materials science. Efficient chemical methods for the synthesis of cyclic peptides with novel three-dimensional structures are highly desired to facilitate the development of this unique class of compounds. However, the range of methods available for constructing peptide macrocycles is limited compared with that for small molecules. We recently developed new methods for synthesizing highly constrained cyclic peptides with C–C crosslinks through Pd-catalyzed C–H activation reactions. These methods use endogenous backbone amides as directing groups and, therefore, have the potential for use in late-stage functionalization of peptide natural products.

A Free Energy Perturbation Approach to Estimate the Intrinsic Solubilities of Drug-like Small Molecules

2019 ◽  
Author(s):  
Sayan Mondal ◽  
Gary Tresadern ◽  
Jeremy Greenwood ◽  
Byungchan Kim ◽  
Joe Kaus ◽  
...  
Keyword(s):  
Solid State ◽  
Small Molecules ◽  
Three Dimensional ◽  
Aqueous Solubility ◽  
Computational Approach ◽  
Free Energy Perturbation ◽  
Perturbation Approach ◽  
Energy Perturbation ◽  
State Form ◽  
Good Agreement

<p>Optimizing the solubility of small molecules is important in a wide variety of contexts, including in drug discovery where the optimization of aqueous solubility is often crucial to achieve oral bioavailability. In such a context, solubility optimization cannot be successfully pursued by indiscriminate increases in polarity, which would likely reduce permeability and potency. Moreover, increasing polarity may not even improve solubility itself in many cases, if it stabilizes the solid-state form. Here we present a novel physics-based approach to predict the solubility of small molecules, that takes into account three-dimensional solid-state characteristics in addition to polarity. The calculated solubilities are in good agreement with experimental solubilities taken both from the literature as well as from several active pharmaceutical discovery projects. This computational approach enables strategies to optimize solubility by disrupting the three-dimensional solid-state packing of novel chemical matter, illustrated here for an active medicinal chemistry campaign.</p>

scholarly journals Second sacral sacralalar‐iliac (S2AI) screw placement in adult degenerative scoliosis (ADS) patients: an imaging study

BMC Surgery ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bing Wu ◽  
Kai Song ◽  
Junyao Cheng ◽  
Pengfei Chi ◽  
Zhaohan Wang ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Imaging Study ◽  
Outer Diameter ◽  
Degenerative Scoliosis ◽  
Female Patients ◽  
Lateral Angle ◽  
Adult Degenerative Scoliosis ◽  
Imaging Characteristics ◽  
Starting Point ◽  
Trajectory Length

Abstract Background The imaging characteristics of sacral sacralalar-iliac (S2AI) screw trajectory in adult degenerative scoliosis (ADS) patients will be determined. Methods S2AI screw trajectories were mapped on three-dimensional computed tomography (3DCT) reconstructions of 40 ADS patients. The starting point, placement plane, screw template, and a circle centered at the lowest point of the ilium inner cortex were set on these images. A tangent line from the starting point to the outer diameter of the circle was selected as the axis of the screw trajectory. The related parameters in different populations were analyzed and compared. Results The trajectory length of S2AI screws in ADS patients was 12.00 ± 0.99 cm, the lateral angle was 41.24 ± 3.92°, the caudal angle was 27.73 ± 6.45°, the distance from the axis of the screw trajectory to the iliosciatic notch was 1.05 ± 0.81 cm, the distance from the axis of the screw trajectory to the upper edge of the acetabulum was 1.85 ± 0.33 cm, and the iliac width was 2.12 ± 1.65 cm. Compared with females, the lateral angle of male ADS patients was decreased, but the trajectory length was increased (P < 0.05). Compared to patients without ADS in previous studies, the lateral angle of male patients was larger, the lateral angle of female patients was increased, and the caudal angle was decreased (P < 0.05). Conclusions There is an ideal trajectory of S2AI screws in ADS patients. A different direction should be noticed in the placement of S2AI screws, especially in female patients.

scholarly journals Therapeutic Advances in Oncology

2021 ◽  
Vol 22 (4) ◽  
pp. 2008
Author(s):  
Jinsha Liu ◽  
Priyanka Pandya ◽  
Sepideh Afshar
Keyword(s):  
Small Molecules ◽  
New Technologies ◽  
Treatment Options ◽  
Current Treatment ◽  
Bispecific Antibodies ◽  
Gene Therapies ◽  
Therapeutic Modalities ◽  
The Past ◽  
Drug Conjugates ◽  
Novel Targets

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.

scholarly journals Colourful Poincaré symmetry, gravity and particle actions

2021 ◽  
Vol 2021 (8) ◽  
Author(s):  
Joaquim Gomis ◽  
Euihun Joung ◽  
Axel Kleinschmidt ◽  
Karapet Mkrtchyan
Keyword(s):  
Field Theory ◽  
Free Particle ◽  
Three Dimensional ◽  
Background Field ◽  
Quantum Field ◽  
Symmetry Factor ◽  
Starting Point ◽  
Poincaré Algebra ◽  
Poincaré Symmetry ◽  
Three Space

Abstract We construct a generalisation of the three-dimensional Poincaré algebra that also includes a colour symmetry factor. This algebra can be used to define coloured Poincaré gravity in three space-time dimensions as well as to study generalisations of massive and massless free particle models. We present various such generalised particle models that differ in which orbits of the coloured Poincaré symmetry are described. Our approach can be seen as a stepping stone towards the description of particles interacting with a non-abelian background field or as a starting point for a worldline formulation of an associated quantum field theory.

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