How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

Abstract

Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4,548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset.

Evaluation of 3-Dimensionality in Approved and Experimental Drug Space

“…The lower energy conformations (black) span 3D scores between 1.1 and 1.4, representing significant topological translations. These findings are in agreement with previous reports stating that a wide range of strain energies can be tolerated by therapeutics when bound to target sites. ,,,, …”

“…The recognition of novel therapeutics by their targets is dictated by ligand–protein interactions. Noncovalent interactions, including hydrogen and halogen bonding, salt bridges, and pi–pi stacking, are typically explored through the development of structure–activity relationships (SAR) to produce potent and selective drugs. − In addition to many protein–ligand interactions that can be optimized, the conformation of inhibitors in the solvated vs bound states can also contribute to the energetic favorability of inhibitor binding. , The diversity of druggable protein targets necessitates structural and conformational variability in ligands to generate effective pharmaceuticals . The amount of molecular strain and associated energy costs tolerated by drugs upon protein binding has been explored, where it was found that molecules binding to proteins could readily incur 5–9 kcal/mol of strain energy .…”

“…Of particular interest is the relationship between the energy minimized/optimized conformations of approved therapeutics and the conformation of those molecules when bound to proteins in the PDB. Previous efforts have focused on the exploration of flexible conformations upon protein binding as they relate to in silico screening and predicting binding conformations rather than the inherent change in 3D topology as described herein. ,, Lastly, we consider the role that inorganic chemistry could play in increasing the prevalence of more 3D molecules in the drug discovery pipeline.…”

“…4,5 The diversity of druggable protein targets necessitates structural and conformational variability in ligands to generate effective pharmaceuticals. 6 The amount of molecular strain and associated energy costs tolerated by drugs upon protein binding has been explored, where it was found that molecules binding to proteins could readily incur 5−9 kcal/mol of strain energy. 5 While extensive rearrangements are possible, increased conformational shape diversity has been related to broad biological activity 7 and successful clinical outcomes.…”

Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery

“…Small molecule conformations need to be sampled to arrive at the correct binding pose. Molecules that appear in binding pockets of substantially different proteins often bind in distinct modes for each protein, suggesting that the binding pose of the molecule need not be near the global energy minima of the molecule ( Nicklaus et al, 1995 ; Boström et al, 1998 ; Perola and Charifson, 2004 ; Sitzmann et al, 2012 ; Friedrich et al, 2018 ). Likewise, in LB pharmacophore modeling, small molecules need to be flexibly aligned according to their chemical properties to identify the biologically relevant 3D features conferring bioactivity.…”