scholarly journals Novel approaches for the rational design of PROTAC linkers

2020 ◽  
Vol 1 (5) ◽  
pp. 381-390
Author(s):  
Almaz Zagidullin ◽  
Vasili Milyukov ◽  
Albert Rizvanov ◽  
Emil Bulatov
Keyword(s):  
Ubiquitin Ligase ◽  
Computer Aided Design ◽  
Rational Design ◽  
E3 Ubiquitin Ligase ◽  
Cell Membrane Permeability ◽  
Structural Components ◽  
Attachment Sites ◽  
Recent Developments ◽  
Improved Stability ◽  
Aided Design

Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC properties, modulate binding kinetics and substantially impacts the potency and selectivity. In this review, the authors briefly discuss the recent findings in PROTAC design approaches with focus on the linker. For each PROTAC such linker parameters as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved stability, bioavailability cell membrane permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase. Thus rational linker design with respect to composition, length and attachment sites is essential for the development of potent PROTAC compounds. Computer-aided design and novel innovative linker strategies, such as PROTAC shortening, photo-switchable PROTACs, in-cell click-formed CLIPTACs, “click chemistry” approaches are also discussed in the review.

WirePATH Rapid Tooling Process and Supporting Software Development

2003 ◽  
Author(s):  
Alexander Lee ◽  
James Brink ◽  
David Anderson ◽  
Karthik Ramani
Keyword(s):  
Computer Aided Design ◽  
Electrical Discharge Machining ◽  
Computer Software ◽  
Wire Edm ◽  
Overall Design ◽  
Design Changes ◽  
Mold Making ◽  
Recent Developments ◽  
New Applications ◽  
Aided Design

Recent developments in Computer Aided Design (CAD) have drastically reduced overall design cycle time and cost. In this paper, wirePATH, a new method for rapid direct tooling, is presented. By using specialized interactive segmentation computer software and wire electrical discharge machining (wire EDM), wirePATH can reduce manufacturing time and cost for injection molds, casting patterns, and dies. Compared to other conventional-mold making methods, wirePATH can reduce fabrication time by as much as 40 to 70%. Wirepath can use a combination of wire EDM and other processes. Our method provides a new means to produce a greater variety in products by changing only portions of the tooling. Segments allow a part of a mold to be replaced to accommodate design changes and repair. WirePATH enables new applications of wire EDM to more complex shapes by bridging the gaps between CAD, our method, wire EDM and conventional manufacturing processes.

Optimal Sensor Design Using Patient-Specific Images

2010 ◽  
Vol 4 (2) ◽  
Author(s):  
Sukhi Basati ◽  
Timothy J. Harris ◽  
Andreas A. Linninger
Keyword(s):  
Computer Aided Design ◽  
Rational Design ◽  
Treatment Options ◽  
Patient Specific ◽  
Data Sets ◽  
Disease States ◽  
Magnetic Resonance Data ◽  
Computer Aided ◽  
Aided Design ◽  
Pathological Disease

In diseases such as hydrocephalus, the cerebral ventricles enlarge. The treatment options for these patients are presently based on pressure, which has limited capabilities. We present the design of a volume sensor as an alternative monitoring option. Through the use of computer aided design and simulation, we optimized a sensor in silico with fewer resources. Specifically, we designed a sensor for animal experimentation with a scalable procedure for human sensors. In this paper, we present a rational design approach for a sensor that integrates advances in medical imaging. Magnetic resonance data sets of both normal and diseased subjects were used as a virtual laboratory. Finite element simulations were performed under pathological disease states of the brain as a contribution toward an accelerated device design. An optimized sensor was then fabricated for these subjects based on the outcome of the simulations. In this paper, we explain how a computer aided subject-specific design was used to help fabricate and test our sensor.

Computer Aided Design and Analysis of Composite Structure

2014 ◽  
Vol 1036 ◽  
pp. 989-994 ◽  
Author(s):  
Michał Majzner ◽  
Andrzej Baier
Keyword(s):  
Layered Structure ◽  
Computer Aided Design ◽  
Object Oriented ◽  
Verification And Validation ◽  
Structural Components ◽  
Modeling And Analysis ◽  
Computer Aided ◽  
The Individual ◽  
Aided Design ◽  
The Relationship

Feature is one of the methods for representing objects from which are representing components, products and processes. This article presents methods for integration of features of methods in modeling and analysis of composite structural components. The aim of the research is to develop methods for verification and validation of composite layered structure, distinguishing components of the individual layers and identify the relationship between them. By applying the method of features it is possible to determine the structure of the composite fit to the requirements of design and construction. Proposed new types of feature, which allows the creation of object-oriented structures of composite components.

Some Perspectives in the Modelling of Biological Treatment of Wastewaters

1982 ◽  
Vol 14 (1-2) ◽  
pp. 227-240 ◽  
Author(s):  
A James
Keyword(s):  
Computer Aided Design ◽  
Biological Treatment ◽  
Activated Sludge Process ◽  
Variable Yield ◽  
Physical Description ◽  
Fixed Film ◽  
Recent Developments ◽  
Operational Models ◽  
Aided Design ◽  
Kinetics Of

This paper reviews some recent developments in the modelling of the biological treatment of wastewaters with particular reference to the activated sludge process. The bacterial kinetics of completely-mixed reactors are discussed emphasising the need to have a variable yield. Modelling complications of variable yields are noted in particular those caused by de-coupling growth and substrate utilization. Other methods of solution are considered including relating the yield to the sludge age. Modelling developments in fixed-film reactors are briefly examined, comparing the refinement in the chemical/physical description with the lack of refinement in the ecological representation. The aims of modelling are reviewed and some fruitful areas in operational models and computer-aided-design are identified.

Recent developments in EDS for TEM/STEM

1988 ◽  
Vol 46 ◽  
pp. 670-671
Author(s):  
J.J. McCarthy
Keyword(s):  
Computer Aided Design ◽  
Gate Valve ◽  
Solid Angle ◽  
Future Directions ◽  
Specimen Holder ◽  
Recent Developments ◽  
Graded Material ◽  
Computer Controlled ◽  
Special Environment ◽  
Aided Design

The development of TEM and STEM in the 100 keV to 400 keV range has prompted the increased use of energy dispersive spectrometers (EDS) for analytical studies on these instruments. The TEM/STEM environment is a harsh one for the EDS in comparison to the SEM. In response to this special environment, spectrometers specifically for TEM/STEM have been developed. This paper will provide a general review of these developments and indicate future directions.Space near the specimen holder is at a premium in most TEMs. This reduces the solid angle subtended by the Si(Li) detector. Increased cooperation between EM and EDS manufacturers, and the use of new materials for shielding, collimation, and internal detector parts have improved this situation. The use of graded material collimators, removable ultra thin windows (UTW), and compact gate valve arrangements can reduce detector size. The routine use of computer aided design (CAD) systems and computer controlled machining allow extremely close tolerances to be incorporated in the latest designs.

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