Rational design

Summary

In chemical biology and biomolecular engineering, rational design (RD) is an umbrella term which invites the strategy of creating new molecules with a certain functionality, based upon the ability to predict how the molecule's structure (specifically derived from motifs) will affect its behavior through physical models. This can be done either from scratch or by making calculated variations on a known structure, and usually complements directed evolution. Applications As an example, rational design is used to decipher collagen stability, mapping ligand-receptor interactions, unveiling protein folding and dynamics, and creating extra-biological structures by using fluorinated amino acids. To treat cancer, rational design is used for targeted therapies where proteins are engineered to modify the communication of cells with their environment. There is also the rational design of alfa-alkyl auxin molecules, which are auxin analogs capable of binding and blocking the formation

Official source

https://en.wikipedia.org/wiki/Rational_design

About this result

This page is automatically generated and may contain information that is not correct, complete, up-to-date, or relevant to your search query. The same applies to every other page on this website. Please make sure to verify the information with EPFL's official sources.

Related publications (67)

Related publications

Related people (8)

Related people

Related units (6)

Related units

Related concepts

Related courses (3)

Related courses

Related lectures (1)

Related lectures

Multivalent Pattern Recognition Through Engineering of Spatial Tolerance in DNA-Based Nanomaterials

Hale Bila

Strength in numbers, combining many weak interactions into an overall strong connection, is the fundamental principle of multivaleny. This concept has been exploiting for the engineering of super-selective cell-targeting materials, which generally display high number of flexible ligands to enhance the systems' avidity. Many biological processes, however, function through a temporal spatial organization of receptors in patterns, matching with a controlled number of ligands to create a specific interaction. In this low-valency regime, the mechanics e.g. rigidity of the ligand-presenting architecture plays a critical role in the selectivity of the multivalent complex. Exploiting the precision in spatial design inherent to DNA nanotechnology, we engineered a library of scaffolds to explore how valency, affinity, and rigidity control the balance of super-selective multivalent binding. Depending on the affinity between the ligand and receptor, a pattern-dependent binding behavior was achieved when spatial tolerance of ligands matches the spatial organization of the target. We label this new form of mechanics-controlled multivalent binding "multivalent pattern recognition" (MPR). The main parameter controlling MPR is the rigidity of the ligand, which controls the over spatial tolerance of binding. Our findings contribute to the rational design of selective targeting with nanomaterials.

EPFL2022

Here we provide a personal account of innovation and design principles underpinning a method to interrogate precision electrophile signaling that has come to be known as "REX technologies". This Account is framed in the context of trying to improve methods of target mining and understanding of individual target-ligand engagement by a specific natural electrophile and the ramifications of this labeling event in cells and organisms. We start by explaining from a practical standpoint why gleaning such understanding is critical: we are constantly assailed by a battery of electrophilic molecules that exist as a consequence of diet, food preparation, ineluctable endogenous metabolic processes, and potentially disease. The resulting molecules, which are detectable in the body, appear to be able to modify function of specific proteins. Aside from potentially being biologically relevant in their own right, these labeling events are essentially identical to protein-covalent drug interactions. Thus, on what proteins and even in what ways a covalent drug will work can be understood through the eyes of natural electrophiles; extending this logic leads to the postulate that target identification of specific electrophiles can inform on drug design. However, when we entered this field, there was no way to interrogate how a specific labeling event impacted a specific protein in an unperturbed cell. Methods to evaluate stoichiometry of labeling, and even chemospecificity of a specific phenotype were limited. There were further no generally accepted ways to study electrophile signaling that did not hugely disturb physiology. We developed T-REX, a method to study single-protein-specific electrophile engagement, to interrogate how single-protein electrophile labeling shapes pathway flux. Using T-REX, we discovered that labeling of several proteins by a specific electrophile, even at low occupancy, leads to biologically relevant signaling outputs. Further experimentation using T-REX showed that in some instances, single-protein isoforms were electrophile responsive against other isoforms, such as Akt3. Selective electrophile-labeling of Akt3 elicited inhibition of Akt-pathway flux in cells and in zebrafish embryos. Using these data, we rationally designed a molecule to selectively target Akt3. This was a fusion of the naturally derived electrophile and an isoform-nonspecific, reversible Akt inhibitor in phase-II trials, MK-2206. The resulting molecule was a selective inhibitor of Akt3 and was shown to fare better than MK-2206 in breast cancer xenograft mouse models. Recently, we have also developed a means to screen electrophile sensors that is unbiased and uses a precise burst of electrophiles. Using this method, dubbed G-REX, in conjunction with T-REX, we discovered new DNA-damage response upregulation pathways orchestrated by simple natural electrophiles. We thus emphasize how deriving a quantitative understanding of electrophile signaling that is linked to thorough and precise mechanistic studies can open doors to numerous medicinally and biologically relevant insights, from gleaning better understanding of target engagement and target mining to rational design of targeted covalent medicines.

AMER CHEMICAL SOC2021

Generation of photoswitchable peptide ligands by phage display

Silvia Bellotto

Photoswitchable ligands are used to control and study complex biological systems such as folding of proteins and peptides, enzymatic reactions or neuronal signaling. They are typically developed by conjugating photochromic compounds to known ligands so that exposure to light results in the change of the binding affinity of the ligand. Many light-responsive ligands are based on azobenzene, a molecule that undergoes a pronounced change in geometry upon photoisomerization from trans to cis in picoseconds. Currently, photoswitchable ligands are available only to a limited number of targets and their development by rational design is complex. Furthermore, they show low affinity and a relatively small change in binding affinity between the cis and trans conformation. In my PhD work, I aimed at overcoming these shortcomings by establishing an in vitro evolution method to generate light-controlled peptide ligands to targets of choice. Combining the expertise on phage display technology of the Heinis' lab and the knowledge about azobenzene photoswitches of the Wegner's lab, I screened large combinatorial libraries of cyclic peptides containing an azobenzene-based linker for the generation of light controlled ligands. [...]

EPFL2015

AMER CHEMICAL SOC2021