Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery—Construction of a Diversity-Optimized Halogen-Enriched Fragment Library

Abstract

Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by V max Pred.

Concepts and Core Principles of Fragment-Based Drug Design

“…Firstly, commercially available fragments and fragment libraries should be analysed. It is important to use a library that meets some primary criteria depending on the profile of the respective target [11]. Usually, commercially available fragment libraries have been selected based on chemical and size diversity, and different, well-balanced properties to cover most of the important features.…”

Application of Fragment-Based Drug Discovery to Versatile Targets

“…Quite a few fragment libraries are commercially available (Singh et al, 2018). Many researchers have built up their own fragment libraries based on their respective experience (Garner et al, 2019;Heidrich et al, 2019). The customized library usually does not contain molecules that are reactive to targets, bind to proteins un-specifically, form aggregate or form covalent bonds with proteins.…”

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…[45] Thus, the use of halogenated (primarily brominated) fragments may significantly enhances creening by X-ray crystallography.H alogena toms may also participate in binding interactions through halogen bonds and are, as such, not necessarily only reporter tags. [46,47] Furthermore, even if ah alogeni sn ot directly involved in binding, it may enable easy synthetic elaboration through various coupling reactions. [48][49][50] SGX Pharmaceuticals (now parto fE li Lilly) wasa mong the first to report the inclusion of brominated fragments to improve both screening by X-ray crystallography and subsequent hit-to-lead chemistry.…”