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. 2014 May 22:6:27.
doi: 10.1186/1758-2946-6-27. eCollection 2014.

Expanding the fragrance chemical space for virtual screening

Affiliations

Expanding the fragrance chemical space for virtual screening

Lars Ruddigkeit et al. J Cheminform. .

Abstract

The properties of fragrance molecules in the public databases SuperScent and Flavornet were analyzed to define a "fragrance-like" (FL) property range (Heavy Atom Count ≤ 21, only C, H, O, S, (O + S) ≤ 3, Hydrogen Bond Donor ≤ 1) and the corresponding chemical space including FL molecules from PubChem (NIH repository of molecules), ChEMBL (bioactive molecules), ZINC (drug-like molecules), and GDB-13 (all possible organic molecules up to 13 atoms of C, N, O, S, Cl). The FL subsets of these databases were classified by MQN (Molecular Quantum Numbers, a set of 42 integer value descriptors of molecular structure) and formatted for fast MQN-similarity searching and interactive exploration of color-coded principal component maps in form of the FL-mapplet and FL-browser applications freely available at http://www.gdb.unibe.ch. MQN-similarity is shown to efficiently recover 15 different fragrance molecule families from the different FL subsets, demonstrating the relevance of the MQN-based tool to explore the fragrance chemical space.

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Figures

Figure 1
Figure 1
Property histograms of various databases (A-D) and their fragrance-like subsets (E-H). The frequency peak in FragranceDB at 9-11 heavy atoms corresponds to a diverse constellation comprising aliphatic linear and branched alkenes, aldehydes, alcohols, ketones and esters, various simple benzene, phenol and benzaldehyde analogs, furanones, monoterpenes. The frequency peaks in TasteDB at 10-12 atoms corresponds to various hexoses and their reduced hexitols, monoterpenes, coumarins, anisols, and amino acids.
Figure 2
Figure 2
Color-coded MQN-maps of subsets GDB-13-FL and ZINC.FL. A. Loadings of PC1, PC2 and PC3 for PCA of FragranceDB. The 42 MQNs are defined as follows: atom counts: c, f, cl, br, i, s, p = elements, an/cn = acyclic/cyclic nitrogens, ao/co = acyclic/cyclic oxygens, hac = heavy atom count, bond counts: asb/adb/atb = acyclic single/double/triple bonds, csb/cdb/ctb = cyclic single/double/triple bonds, rbc = rotatable bond count, polarity counts: hba/hbd/hbam/hbdm = H-bond acceptor/donor atoms/sites, pos/neg = positive/negative charges at pH 7.4, topology counts: asv/adv/atv/aqv = acyclic monovalent/divalent/trivalent/tetravalent nodes, cdv/ctv/cqv = cyclic divalent/trivalent/tetravalent nodes, ri = i-membered rings (i = 3-9), rg10 = ≥10-membered rings, afr/bfr = atoms/bonds shared by fused rings. ri, rg10 and afr/bfr are counted in the smallest set of smallest rings.B. Color-coded maps for GDB-13.FL. Note that the carbon count decreases at right because heteroatom rich compounds take over. C. Color-coded maps for ZINC.FL. Color-coding represents the increasing value of the indicated property in the scale blue-cyan-green-yellow-orange-red-magenta. Interactive color-coded MQN-maps for all FL subsets can be accessed with the FL-mapplet at http://gdb.unibe.ch.
Figure 3
Figure 3
LBVS of fragrance molecule analogs (15 sets from Table2). A. Average AUC ± σ for recovery of the 15 fragrance molecule sets from the corresponding reference using MQN, Sfp, ECfp4 or MW. B. Average percentage of actives recovered ± σ at the indicated database coverage. C-F. Average cumulative recovery of actives and average coverage of each database as a function city-block distance from the reference compound of each active set, in MQN-space (CBDMQN, C), Sfp-space (CBDSfp, D), ECfp4-space (CBDECfp4, E), and MW-space (CBDMW, F). ROC-curves for each fragrance molecule family are available in the Additional file 1.
Figure 4
Figure 4
MQN-nearest neighbour isomers of menthone (hit no. 1) in the ZINC database preserving the same number of H-bond donor atoms (0) and H-bond acceptor atoms (1).

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