Evaluation of 3-Dimensionality in Approved and Experimental Drug Space

Abstract

The 3-dimensional (3D) structure of therapeutics and other bioactive molecules is an important factor in determining the strength and selectivity of their protein–ligand interactions. Previous efforts have considered the strain introduced and tolerated through conformational changes induced upon protein binding. Herein, we present an analysis of 3-dimentionality for energy-minimized structures from the DrugBank and ligands bound to proteins identified in the Protein Data Bank (PDB). This analysis reveals that the majority of molecules found in both the DrugBank and the PDB tend toward linearity and planarity, with few molecules having highly 3D conformations. Decidedly 3D geometries have been historically difficult to achieve, likely due to the synthetic challenge of making 3D organic molecules, and other considerations, such as adherence to the ‘rule-of-five’. This has resulted in the dominance of planar and/or linear topologies of the molecules described here. Strategies to address the generally flat nature of these data sets are explored, including the use of 3D organic fragments and inorganic scaffolds as a means of accessing privileged 3D space. This work highlights the potential utility of libraries with greater 3D topological diversity so that the importance of molecular shape to biological behavior can be more fully understood in drug discovery campaigns.

Metal complexes for therapeutic applications

“…Current drug discovery efforts typically rely on high-throughput screening (HTS) or fragment-based drug discovery (FBDD) to identify bioactive compounds [34]. Despite the advantages of highly 3D molecules, modern drug discovery relies heavily on 2D and planar structures for both fragment and lead-like molecules [30,32,35]. Although there have been many recent efforts to design libraries comprising highly 3D molecules for drug discovery purposes [28,33,[36][37][38], most drug-like molecules trend toward planarity [32].…”

DrugSpaceX: a large screenable and synthetically tractable database extending drug space

“…As shown in Figure 2C , the compounds of DrugSpaceX were subjected to the above shape analysis, and the results were compared with the data from the Drug Set. This figure shows that the vast majority of approved small molecule drugs are either rodlike or disklike, while the DrugSpaceX database densely populates the third dimension in shape space, suggesting that it contains many more scaffold types and spherical molecules that are rare in conventional compound libraries ( 45 ). Due to the application of transformation rules, the shape diversity of compounds reflects the transformation of drugs at different positions.…”

Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

“…[2,3] Moreover complexity (as measured by fraction sp 3 )a nd the presence of chiral centers correlates with success as compounds transition from discovery,through clinical testing,todrugs. [4] Considering these factors,b ridged bicyclicn itrogen scaffolds have ah uge potential in drug discovery,a se xemplified with varenicline and tiotropium bromide commercial drugs featured in the top 200 pharmaceutical sales list of 2020. [5] Among these bridged bicyclicn itrogen scaffolds,t he normorphan (6-azabicyclo[3.2.1]octane) skeleton is especially attractive due to its rigidity,3-dimensionality,high sp 3 carbon fraction (F sp 3 ), [4] and low molecular weight.…”

“…[4] Considering these factors,b ridged bicyclicn itrogen scaffolds have ah uge potential in drug discovery,a se xemplified with varenicline and tiotropium bromide commercial drugs featured in the top 200 pharmaceutical sales list of 2020. [5] Among these bridged bicyclicn itrogen scaffolds,t he normorphan (6-azabicyclo[3.2.1]octane) skeleton is especially attractive due to its rigidity,3-dimensionality,high sp 3 carbon fraction (F sp 3 ), [4] and low molecular weight. [6] Moreover,i t forms the backbone of several natural products (Figure 1) and appears as as ubunit in numerous alkaloids such as D-normorphinans, C-norbenzomorphans,s arain A, and hetisine.…”