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_maxPred.

Keywords: HEFLib; Vmax; design; diversity; fragment; library.

Figure 1

Electrostatic potential (ESP) plots of different halogen-bearing aromatic ring systems with net charge of null. ESP from −0.34 au (dark blue) via zero (white) to +0.34 au (red). Example molecules out of generated HEFLib: (A) 5,6-dichloro-4-pyrimidinamine and (B) 2-bromo-4-nitro-1H-imidazole.

Figure 2

Schematic depiction of feature tree-like comparison of two molecules (I,II). Comparison node-based on aromatic ring (yellow) that carries halogen (blue) and defines the central molecular property, hydrogen bond acceptors and donors (green and red), ring structures (orange), and linkers (gray). Rooted comparison of ortho, meta, and para sub tree of molecule I and II ($T_{o,m,p}^{I,II}$).

Figure 3

Structural formula and 3D depictions of electrostatic potentials, illustrating similarities and diversities with respect to chemotype and XB interface (binding motif). Three examples from the herein presented showcase HEFLib are shown. Pharmacophoric arrows indicate typical vectors of electrophilic attack toward the ligand (blue) or toward the target by σ-hole interactions (red). Upon shifting the pyridine-type nitrogen atom from position 5 in 3-bromoimidazo[1,2-b]pyridazine (A) to position 7 in 3-bromoimidazo[1,2-a]pyrazine (B), electron density is withdrawn from the negative belt of the halogen toward the opposite direction of the σ-hole. Consequently, a much larger positive electrostatic potential representing a significantly tuned σ-hole with reduced directionality is characteristic for the halogen bonding interface of (B). In case of 5,6-dichloropyrimidin-4-amine (C) the same molecule offers one classical XB interface with addressable electron density around the halogen atom and one significantly tuned halogen bonding interface. Despite significant differences in the chemotype, the XB interface of (A) and the classical XB interface of (C) share some obvious similarities.

Figure 4

Distribution of number of heavy atoms (RDKit), molecular weight (Canvas Molecular Descriptors, Schrödinger), number of hydrogen bond acceptors (CDK), number of hydrogen bond donors (CDK), number of rotatable bonds (CDK, non-terminal), SlogP as cLogP (RDKit) and Topological Polar Surface Area (Ertl et al., 2000) (RDKit). Dashed red lines indicate mean values (μ). Green bars indicate bins that fulfill rule of three (Congreve et al., 2003). Density shown for continuous data.

Figure 5

Shape distribution of HEFLib with n = 198. Geometry optimization by LigPrep (Schrödinger Release., 2018) (Schrödinger) and OPLS2005. sp3 character calculated with CDK (Steinbeck et al., , ; Willighagen et al., 2017). PMI (Sauer and Schwarz, 2003) calculation with Vernalis Nodes for KNIME.

Figure 6

Depicted structures with high structural similarity, but significantly different XB interface: (A) 3-bromoimidazo[1,2-a]pyrazine and (B) 3-bromoimidazo[1,2-b]pyridazine. Electrostatic potential plot colored from −0.34 au (blue) via zero (white) to +0.34 au (red). Magnitude: V_{max, A} = 0.040 au, V_{max, B} = 0.028 au. Deviation of point of V_max from C-X bond vector linearity: Φ(V_{max, A}) = 2.0°, Φ(V_{max, B}) = 4.6°.

Figure 7

Distribution of V_max of neutral isomers in the showcase HEFLib. Color encodes the type of aromatic halogen: Green for chlorine, brown for bromine, and purple for iodine. Same color code is used for reference V_max values (dashed lines) of chloro-, bromo-, and iodobenzene. Extreme values are found for zwitterionic fragments.