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Abstract
(1) Background: Compounds with multitarget activity are of interest in basic research to explore molecular foundations of promiscuous binding and in drug discovery as agents eliciting polypharmacological effects. Our study has aimed to systematically identify compounds that form complexes with proteins from distinct classes and compare their bioactive conformations and molecular properties. (2) Methods: A large-scale computational investigation was carried out that combined the analysis of complex X-ray structures, ligand binding modes, compound activity data, and various molecular properties. (3) Results: A total of 515 ligands with multitarget activity were identified that included 70 organic compounds binding to proteins from different classes. These multiclass ligands (MCLs) were often flexible and surprisingly hydrophilic. Moreover, they displayed a wide spectrum of binding modes. In different target structure environments, binding shapes of MCLs were often similar, but also distinct. (4) Conclusions: Combined structural and activity data analysis identified compounds with activity against proteins with distinct structures and functions. MCLs were found to have greatly varying shape similarity when binding to different protein classes. Hence, there were no apparent canonical binding shapes indicating multitarget activity. Rather, conformational versatility characterized MCL binding.
Highlights
Small molecules with activity against multiple targets, termed promiscuous compounds [1], are of increasing interest in pharmaceutical research because they are able to elicit polypharmacological effects that often contribute strongly to the efficacy of drugs [2,3,4,5]
We have reported a large-scale data analysis designed to identify promiscuous compounds binding to different protein classes
The set of multiclass ligands (MCLs) we newly identified was thoroughly characterized focusing on binding modes and molecular properties in comparison to single-class ligands (SCLs), which we assembled
Summary
Small molecules with activity against multiple targets, termed promiscuous compounds [1], are of increasing interest in pharmaceutical research because they are able to elicit polypharmacological effects that often contribute strongly to the efficacy of drugs [2,3,4,5]. The most reliable approach to confirm multitarget activity of small molecules and explore binding events at the molecular level of detail is analyzing and comparing three-dimensional structures of ligand-target complexes [14,15]. It has been shown, for example, that promiscuous compounds often bind to similar protein domains and binding sites [15,16,17], as one might anticipate. Ligands were chemically diverse (>98% non-analog ligands) and frequently displayed similar binding modes interacting with different proteins (median root mean square deviation (RMSD): 1 Å) They typically formed different interaction hotspots in binding sites [19].
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