Probing secondary interactions in biomolecular recognition by dynamic combinatorial chemistry

Abstract

Artificial multivalent recognition systems offer promising perspectives for developing synthetic compounds capable of interacting effectively and selectively with biomolecules in aqueous medium. The identification of multi-point binding ligands requires screening of a large number of complex structures, with different spacers, different ligands, and varying valency. This represents a challenge for rational design approaches. On the other hand, the use of dynamic covalent chemistry enables a target-driven one-pot screening approach for probing secondary interactions, thereby facilitating the identification of multivalent recognition systems that optimally combine multiple fragments. Herein we review the recent developments in the implementation of dynamic combinatorial chemistry for probing secondary interactions and thereby identify multi-point binding ligands of biomolecules.

Degradable Hybrid Materials Based on Cationic Acylhydrazone Dynamic Covalent Polymers Promote DNA Complexation through Multivalent Interactions

“…[22] Dynamic covalent polymers may also be considered as smart materials for the multivalent recognition of biomolecules. [23] Indeed, the repeated incorporation of multiple functional monomers into a single structure may lead to the multivalent presentation of several binding units in their polymer states, whereas monomers alone should display a weaker affinity for the target due to their reduced valency. [24] Dynamic covalent polymers may therefore serve as smart multivalent vectors, the degradation of which, upon a physicochemical trigger, leads to the release of the therapeutic agent and generates smaller components that may be more easily eliminated from the body.…”

Protein‐Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

“…[86,99] Thestability of the ligation products of nitrogen nucleophiles with aldehydes is further elevated in the case of hydroxylamines,h ydrazines, and acyl hydrazides. [14,77,[86][87][88][89][90][91][92][93][94][95][96][97]100] Theformed products,oximes and (acyl) hydrazones,a re stable at physiological pH values and can be isolated by standard procedures,s uch as column chromatography.A ccordingly,t he ligation reaction is equilibrated very slowly or aniline has to be added as acatalyst for the formation of the hydrazine or oxime. [86,87,89,99] Alternatively,the equilibration of acyl hydrazones can be accelerated by the addition of acid.…”

“…In Section 4wewill give an overview of the chemical reactions used so far in templated ligations and also discuss possible future extensions of this reaction set. Reversible reactions, which have been studied in the context of dynamic covalent chemistry [7][8][9][10][11][12][13][14] and irreversible reactions,also denominated as target-guided synthesis (TGS), [15] are treated together,a sb oth reaction categories deliver examples of templated fragment ligations and in many cases it is difficult to categorize one reaction unambiguously.R epresentative recent applications of templated ligations in fragment-based drug discovery are reported in Section 5, thus demonstrating how far the method has developed to date.F inally,i n Section 6w ew ill discuss the current state of protein-templated fragment ligations,considering the strengths of this method and the requirements for it to succeed. Thec omplementarity of the method with classical ligand screening and fragment-based methods will be considered, thereby leading to an outlook on the relevance and further development of proteintemplated fragment ligations for future drug discovery.…”

New insights into the kinetic target-guided synthesis of protein ligands

“…The process is divided into two major concepts: the thermodynamically controlled involving reversible reactions also known as dynamic combinatorial chemistry (Fig. 1A) 6,7 and the kinetically controlled reactions involving irreversible bond formation 8,9 Both have proved their efficiency in drug discovery. Particularly, in the kinetic TGS (KTGS) approach, best fragments from each binding site of the biomolecule would preferentially react together due to their spatial proximity, and lead to the corresponding dimeric ligand displaying synergistic bioactivity (Fig.…”