The lines correspond to the mass spectrum from the NIST database [ 15 ]. With the exception of a strong contribution at 18 amu H 2 O , our data is consistent with Ref. Figure 4 Partial ion yield at the C 1 s edge of L-alanine. The solid line is the measured partial ion yield signal, the dotted line is a theoretical calculation [ 24 ]. The left scale refers to the measured ion yields, while the right scale Mb refers to the theoretical data.
The lower plot shows the difference in the cross sections for light of opposite helicities. The photon energy resolution was better than meV full width at half maximum FWHM during this scan. The arrow indicates the energy of the CD measurement.
Figure 5 Partial ion yield of D-serine at the C 1 s edge. The solid line is the measured partial ion yield signal, the dotted line is theory [ 24 ]. The chemical shifts of the different C 1 s edges are clearly resolved and contribute differently to the different fragment masses not shown here. This spectrum contains strong contributions of H 2 O coming from the oven, as the sample drying procedure was too short in this case. Figure 8 A simple model for CD of amino acids attached to dust particles: If the molecules are attached with the same chemical group to a surface, e.
Thus CD is also possible in the dipole approximation. Due to the importance of 3D-molecular shape and pharmacophores in determining the bioactivity [ 17 - 25 ] and clinical success of small molecule drugs, [ 26 ] we recently expanded our city-block distance based search algorithm to the topological atom pair fingerprints APfp bit atom pair fingerprint, all heavy atoms without categories and Xfp bit category extended atom pair fingerprint , which count the number of atom pairs at increasing topological distance, counted in bonds through the shortest path, following a concept originally reported by Carhart et al.
APfp and Xfp were computed from the 2D-structure only.
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Considering that the 3D-structure of molecules is now available in several large databases such as the Cambridge Structural Database CSD, experimental X-ray crystal structure or the collated catalogs of all commercial compounds ZINC, predicted 3D-structures , it should also be possible to compute a related 3D-atom pair fingerprint considering through-space rather than topological distances between atoms and subsequently organize large databases for fast LBVS. Such 3D-fingerprints should represent the actual 3D-shape more closely than 2D-fingerprints, and enable stereoselective LBVS by distinguishing between different conformers and stereoisomers of the same molecule, which is not possible with 2D-fingerprints.
Sheridan et al.
Stereoselectivity in the Wittig Reaction
Fingerprint based LBVS for these analogs showed that the very compact, bit shape-only fingerprint 3DAPfp performed best among all fingerprints for recovering Shape and Comboscore analogs. In a second study recovering actives in the directory of useful decoys DUD , a broadly accepted method to benchmark virtual screening methods, [ 40 - 44 ] 3DXfp again performed better than 3DAPfp, yet showed results comparable to its parent 2D-fingerprint Xfp, an effect which might be related to the very 2-dimensional nature of the molecules in DUD and ZINC.
Remarkably, the 3D-fingeprints were stereoselective and produced significant differences between conformers and stereoisomers of the same molecule compared to different molecules of similar size. A third study was therefore performed in which the 3D-fingerprints were used for LBVS starting from different diastereomers of chiral drugs. Both 3DXfp and 3DAPfp gave very different nearest neighbors from different diastereomers, which were also different from the nearest neighbours obtained by the parent 2D-fingerprint search with Xfp or APfp, highlighting the impact of stereochemistry on LBVS.
The 3D-fingerprints were designed in direct analogy to our recently reported 2D atom pair fingerprints, with a simple version tailored for shape similarity with all heavy atoms treated equally 3DAPfp , and an atom category extended version 3DXfp tailored for pharmacophore similarity, considering hydrophobic atoms Hyb , H-bond donors HBD , H-bond acceptors HBA , planar atoms sp 2 , and the HBD-HBA cross-pair as categories.
Theory of Orientation and Stereoselection | K. Fukui | Springer
In contrast to 2D-fingerprints for which distance bins are automatically defined by the topological distance counted in number of bonds through the shortest path, 3D-fingerprints require a binning principle for the through-space distance to assign atom pairs to distance bins. Following an approach similar to that of Sheridan et al. The atom pair bit value increments were summed, and the sum values normalized to HAC 1.
To test if this concept was useful, two additional 3D-fingerprints were created by simply binning the distance at regular 0. Distance sampling for 3D-atom pair fingerprints illustrated for atom-pair distance of 8. A gaussian curve is drawn red with its maximum centred at atom-pair distance of 8. The gaussian is then sampled at 16 distance values B1-B16 blue vertical bars : 1.
Regular Binning: the atom-pair distance of 8. Bit values B1-B16 for the atom pair at 8. LBVS for 3D-shape and pharmacophore analogs using the various fingerprints was tested for , organic molecules up to 50 atoms from the Cambridge Structural Database CSD, which reports experimentally determined 3D coordinates covering a broad range of molecular shapes as measured by the normalized principal moment of inertia nPMI triangle, [ 17 ] including significant coverage of disk-like and spherical shapes.
For each of the three cases A-C , the frequency histogram of AUC values for various fingerprints is shown on left, and the average AUC value as a function of position in the shape triangle for various fingerprints is shown on right. The shape triangle results from plotting the normalized moment of inertia of molecules and distinguishes rod-like, disc-like and sphere-like shapes. For cases where the AUC values were higher for 3DAPfp than for APfp such as compounds 1 — 4 , a folded conformation was observed in the crystal structure.
In such folded structures topological distances overestimate the actual through-space distances separating atom pairs, explaining the lower performance of the 2D-fingerprint.
This effect is difficult to rationalize because it occurs independent of molecular shape in both planar e. The recovery of DUD actives from decoys and from the entire ZINC database was investigated as a second test for fingerprint performance [ 40 - 44 ]. For each DUD active set the molecule closest to all other actives in the set in the corresponding fingerprint space was used as reference molecule for the recovery study. Recovery of DUD actives using various fingerprints.
The various 3D atom pair fingerprints readily retrieved scaffold-hopping analogs, which are compounds with high shape and pharmacophore similarity, similar bioactivity, but a low level of substructure similarity as measured by substructure similarity comparisons Sfp [ 45 ]. Similar scaffold-hopping capabilities were reported previously with MQN, APfp and Xfp, and generally occur with fingerprints not taking detailed substructures into account.
The very low shape diversity in these databases might partly contribute to the similar LBVS performance of 3D and 2D methods with DUD also noted in previous literature reports [ 18 , 33 , 41 , 42 , 46 - 49 ]. A distinctive feature of 3D-scoring functions and fingerprints is their ability to distinguish between different stereoisomers and conformers of the same molecule.
However they lacked chiral sense information and did not differentiate between mirror image conformers, a possibility offered by ROCS scoring functions computed from overlapping chiral 3D-structures Additional file 1 : Figure S9. To test if the stereoselectivity of 3D-fingerprints might influence LBVS, 66 marketed drugs with two stereocenters were identified in Drugbank, and the lowest energy conformer was generated using Omega for each of the two possible diastereomers RR and RS [ 50 ].
In both cases the diastereomers presented large aromatic substituents in opposite relative orientation in space in the minimum energy 3D-conformation used for LBVS. The remaining drugs gave decreasingly stereoselective search results reflecting increasing 3D-shape similarity between the RR and RS diastereomers. In all cases the 3D and 2D-fingerprint searches were almost entirely different, illustrating the different shape perception from through-space versus topological distances.
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The very different nearest neighbors of diastereomeric drugs confirmed the ability of the 3D-atom pair fingerprints to represent stereochemistry and conformation and underscored their importance in LBVS from 3D-structures. The drugs DrugBank code on x-axis are sorted by decreasing number of RR-unique analogs. To illustrate this point 10 ligands bound to their target protein in a folded conformation were identified by searching the Protein Databank for small molecules with very low correlation coefficient between through-space distance between atom pairs in the 3D-structure of the conformer and the corresponding atom pair topological distances in the parent 2D-structure Additional file 1 : Figure S In all 10 cases similarly folded conformations were generated from the Open Eye Omega 3D-builder with which the 3D-structures in ZINC were computed , implying that folding was intrinsic and not induced by protein binding.
In the case of arachidonic acid 19 bound to the adipocyte lipid-binding protein, 3DXfp proposed as second rank analog hexanoic acid 20 with a hydrophobic and bulky tricyclic aromatic group at position 6 mimicking the folded aliphatic chain of Sfp by contrast retrieved simple straight-chain unsaturated carboxylic acids such as the all- trans eicosatetraenoic acid 22 at rank 2, a trend which was also present in Xfp analogs where topological distance perception favoured linear chain analogs, nevertheless many of these straight chain analogs presented a similarly folded conformation.
In the case of bromodomain inhibitor 23 the closest neighbor in 3DXfp space was the unusual scaffold-hopping analog Xfp and Sfp nearest neighbors by contrast were standard substructure analogs such as 25 rank 2 and 26 rank 2 presenting the same folded conformation. The folded conformation of analogs 22 , 25 and 26 retrieved by 2D-fingerprints illustrates that conformational preferences including folding are often enforced by the 2D-structure and therefore indirectly perceived by 2D-fingerprints.
Taken together, the data showed that 3D-fingerprints performed very differently from 2D-fingerprints when searching for analogs of folded molecules, in particular by pointing to analogs with very different scaffolds but realizing similar occupancy of 3D-space. Example of protein bound folded molecules and closest analogs rank 1 or 2 identified in ZINC by 3D- and 2D-fingerprint similarity. See also Additional file 1 : Figures S10 and S These options can be used to add pharmacophore criteria to the shape-only 3DAPfp search, and to enforce electrostatic charge information, which is not encoded in the fingerprints.
Graphical user interface of the 3DXfp browser at www. Result window displaying the 3DXfp nearest neighbors of Clofedanol. The search results are limited to a maximum of molecules to avoid stalling of the internet browser. For each of the result molecules, a link option is available to visualize the data in the parent ZINC database. The interactive browsers provide a straightforward method to rapidly interrogate ZINC for 3D-shape and 3D-pharmacophore analogs of any molecule of interest.
Extending on the work of Sheridan et al.
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An interactive browser was assembled for searching through the All the calculations were performed on 3D structural information available in downloaded SDF files. If the compound was available in complex form, only one of the largest fragments was retained.
The summed bit-values were divided by HAC heavy atom count , multiplied by , and rounded to the integer value. Solvent-dependent divergent functions of Sc OTf 3 in stereoselective epoxide-opening spiroketalizations. Sharma, I. Stereoselective synthesis of acortatarins A and B.
Wurst, J. Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals. Stereoselective synthesis of benzannulated spiroketals: Influence of the aromatic ring on reactivity and conformation. Liu, G. Stereocontrolled synthesis of spiroketals via Ti O i -Pr 4-mediated kinetic spirocyclization of glycal epoxides with retention of configuration.
Theory of orientation and stereoselection
Moilanen, S. Stereocontrolled synthesis of spiroketals via a remarkable methanol-induced kinetic spirocyclization reaction. Potuzak, J.