Evaluation of 3-Dimensionality in Approved and Experimental Drug Space
| Autor: | Ryjul W. Stokes, Kathleen E. Prosser, Seth M. Cohen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Protein Data Bank (RCSB PDB)
Computational biology Plasma protein binding protein-ligand interactions 01 natural sciences Biochemistry 3-dimensionality 03 medical and health sciences Medicinal and Biomolecular Chemistry Drug Discovery 030304 developmental biology 0303 health sciences Experimental drug 010405 organic chemistry Chemistry Drug discovery Organic Chemistry computer.file_format Pharmacology and Pharmaceutical Sciences Protein Data Bank Planarity testing 0104 chemical sciences conformations Generic health relevance DrugBank computer Curse of dimensionality |
| Zdroj: | ACS medicinal chemistry letters, vol 11, iss 6 ACS Med Chem Lett |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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