# QSAR Study of Skin Sensitization Using Local Lymph Node Assay Data

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## Abstract

**:**

## Introduction

## Materials and Methods

**from Accelrys, Inc (Accelrys, San Diego, USA, http://www.accelrys.com/cerius2). The Dragon 2.1 software developed by Milano Chemometrics and QSAR Research Group was used to calculate a total of 1204 molecular descriptors (http://www.disat.unimib.it/chm/Dragon.htm), for each of the studied compounds. The statistical analysis was carried out using the SAS 8.2 statistical package [7].**

^{2}**X**) represents the risk for a given value of X in single variable logistic regression models. Depending on the choice of cumulative distribution function F, the probability of positive response of the LLNA sensitization test P{S=1|X

_{1}, X

_{2}, …, X

_{N}} = F(X`β) – can be represented either by the probit or the logistic regression model [8]. In the present study, we used the logistic regression model, where π(X) = P{S=1|X

_{1}, X

_{2}, …, X

_{N}} that depends on molecular descriptors X

_{1}, X

_{2}, …, X

_{N}, is modeled in the form

_{0}, β

_{1}, …, β

_{N}are regression coefficients.

## Results and Discussion

No. | Symbol | Definition | Class of Descriptors | P-Value |

1 | C-003 | CHR3 | Atom-centered fragments | 0.0005 |

2 | RDF040p | Radial Distribution Function –4.0 / weighted by atomic polarizabilities | RDF | 0.0024 |

3 | nDB | Number of double bonds | Constitutional | 0.0029 |

4 | RDF040v | Radial Distribution Function –4.0 / weighted by atomic van der Waals volumes | RDF | 0.0039 |

5 | TI2 | Second Mohar index TI2 | Topological | 0.0040 |

6 | GATS6m | Geary autocorrelation – lag 6 / weighted by atomic masses | 2D autocorrela-tions | 0.0042 |

7 | Rtu+ | R maximal index / unweighted | GETAWAY | 0.0045 |

8 | RTe+ | R maximal index / weighted by Sanderson electronegativities | GETAWAY | 0.0049 |

9 | BEHp2 | Highest eigenvalue n. 2 of Burden matrix / weighted by atomic polarizabilities | BCUT | 0.0051 |

10 | RDF050e | Radial Distribution Function –5.0 / weighted by atomic Sanderson electronegativities | RDF | 0.0061 |

11 | X3v | Valence connectivity index chi-3 | Topological | 0.0061 |

12 | S2K | 2-path Kier alpha-modified shape index | Topological | 0.0070 |

13 | RDF065p | Radial Distribution Function –6.5 / weighted by atomic polarizabilities | RDF | 0.0072 |

14 | X1v | Valence connectivity index chi-1 | Topological | 0.0074 |

15 | E2m | 2nd component accessibility directional WHIM index / weighted by atomic masses | WHIM | 0.0078 |

16 | Htp | H total index / weighted by atomic polarizabilities | GETAWAY | 0.0082 |

17 | RDF075p | Radial Distribution Function –7.5 / weighted by atomic polarizabilities | RDF | 0.0082 |

18 | X0v | Valence connectivity index chi-0 | Topological | 0.0085 |

19 | RDF075v | Radial Distribution Function –7.5 / weighted by atomic van der Waals volumes | RDF | 0.0089 |

20 | RDF065u | Radial Distribution Function –6.5 / unweighted | RDF | 0.0092 |

21 | RDF050u | Radial Distribution Function –5.0 / unweighted | RDF | 0.0095 |

22 | BEHe2 | Highest eigenvalue n. 2 of Burden matrix / weighted by Sanderson electronegativities | BCUT | 0.0097 |

_{3}groups, in fact, do define molecular sub-fragments that can be considered as ‘structure making’ factors. For example, the number of double bonds between two carbon atoms is associated with the cis-trans isomerism or may indicate the presence of an aromatic ring. The number of double bonds might also be associated with the hydrophobicity and reactivity of the studied compounds. Another important structural element, which contains a double bond, is the carbonyl C=O group. The C-003 descriptor, which is a counter of the CHR

_{3}groups or strictly speaking tertiary carbon atoms, also points at structural motifs that seem to be important in determination of the molecular shape, which is particularly important in the study of skin sensitization.

**Table 2.**Comparison of the best performing logistic models containing 1, 2, 3 and 4 descriptors. Most of presented descriptors are described in Table 1 or in the text, apart from: BELv2, which is a BCUT descriptor weighted by atomic van der Waals volumes; Mor13m, which is a 3D-Morse descriptor weighted by atomic masses; TIE is E-state topological parameter, and C-002 is a counter of CH

_{2}R

_{2}molecular sub-fragments.

Model | Percentage of correctly predicted responses | |

Cross validation | Model | |

GATS6m | 59% | 65% |

BELv2, Mor13m | 69% | 76% |

nDB, C-003, GATS6m | 76% | 78% |

nDB, TIE, C-003 | 70% | 74% |

E2m, TI2, C-003 | 74% | 78% |

E2m, RTe+, C-003 | 70% | 72% |

nDB, C-003, E2m, C-002 | 79% | 80% |

nDB, GATS6m, HATS6e, C-003 | 79% | 83% |

nDB, RTe+, E2m, C-003 | 78% | 78% |

nDB, C-003, GATS6m, TIE | 78% | 80% |

- nDB is the number of double bonds.
- GATS6m is the mass-weighted Geary graph spatial autocorrelation coefficient of the sixth lag. The Geary coefficient is a distance-type function varying from zero to infinity. Strong autocorrelation produces low values of this index; moreover, positive autocorrelation translates into values between 0 and 1 whereas negative autocorrelation produces values larger than 1.
- HATS6e is the GETAWAY descriptor weighted by the atomic Sanderson electronegativities. This descriptor encodes information about molecular shape, size, and atom distribution. Application of the Sanderson electronegativities as weighting coefficients, takes into account, to some degree, charge distribution inside a molecule.
- C-003 is the atom-centered fragments descriptor, indicating the presence of the CHR
_{3}molecular sub-fragment.

Percentage of correctly predicted responses | Percentage of correctly identified active compounds | Percentage of correctly identified inactive compounds | |

Model | 83% | 72% | 93% |

Cross validation | 79% | 68% | 90% |

No. | Compound | CAS | LLNA | Predicted skin sensitization |

1 | chlorobenzene | 108-90-7 | 0 | 0 |

2 | geraniol | 106-24-1 | 0 | 1 |

3 | phenol | 108-95-2 | 0 | 0 |

4 | 2-chloroethanol | 107-07-3 | 0 | 0 |

5 | benzaldehyde | 100-52-7 | 0 | 1 |

6 | 1-bromobutane | 109-65-9 | 0 | 0 |

7 | 1-butanol | 71-36-3 | 0 | 0 |

8 | 2-4-dichloronitrobenzene | 611-06-3 | 0 | 0 |

9 | isopropanol | 67-63-0 | 0 | 0 |

10 | glycerol | 56-81-5 | 0 | 0 |

11 | hexane | 110-54-3 | 0 | 0 |

12 | streptozotocin | 18883-66-4 | 0 | 0 |

13 | 4-aminobenzoic acid | 150-13-0 | 0 | 0 |

14 | 2-acetamidofluorene | 53-96-3 | 0 | 0 |

15 | benzalkonium chloride | 8001-54-5 | 0 | 0 |

16 | dimethyl-isophthalate | 1459-93-4 | 0 | 0 |

17 | ethyl-methanesulfonate | 62-50-0 | 0 | 0 |

18 | 4-hydroxybenzoic acid | 99-96-7 | 0 | 0 |

19 | lactic acid | 598-82-3 | 0 | 0 |

20 | 4-methoxyacetophenone | 100-06-1 | 0 | 0 |

21 | 6-Methylcoumarin | 92-48-8 | 0 | 0 |

22 | methyl-4-hydroxybenzoate | 99-76-3 | 0 | 0 |

23 | methyl salicylate | 119-36-8 | 0 | 0 |

24 | 2-nitrofluorene | 607-57-8 | 0 | 0 |

25 | propylene glycol | 57-55-6 | 0 | 0 |

26 | propyl paraben | 94-13-3 | 0 | 0 |

27 | resorcinol | 108-46-3 | 0 | 0 |

28 | salicylic acid | 69-72-7 | 0 | 0 |

29 | di-2-furanylethanedione | 492-94-4 | 0 | 0 |

30 | 12-bromo-1-dodecanol | 3344-77-2 | 1 | 1 |

31 | 3-amino-5-mercapto-1,2,4-triazole | 16691-43-3 | 1 | 0 |

32 | chloramine-T | 127-65-1 | 1 | 1 |

33 | benzocaine | 94-09-7 | 1 | 0 |

34 | urushiol V | 53237-59-5 | 1 | 1 |

35 | 2-aminophenol | 95-55-6 | 1 | 0 |

36 | phthalic anhydride | 85-44-9 | 1 | 1 |

37 | cinnamic aldehyde | 104-55-2 | 1 | 1 |

38 | camphorquinone | 10373-78-1 | 1 | 1 |

39 | 2-hydroxyethyl-acrylate | 818-61-1 | 1 | 1 |

40 | N-nitroso-N-methylurea | 684-93-5 | 1 | 1 |

41 | diethyl-sulfate | 64-67-5 | 1 | 1 |

42 | 1-2-Benzisothiazol-3[2H]-one | 2634-33-5 | 1 | 1 |

43 | butyl-glycidil ether | 2426-08-6 | 1 | 0 |

44 | methyl-2-nonynoate | 111-80-8 | 1 | 1 |

45 | 2-vinylpyridine | 100-69-6 | 1 | 1 |

46 | propyl gallate | 121-79-9 | 1 | 0 |

47 | ethylene-glycol-dimethacrylate | 97-90-5 | 1 | 0 |

48 | imidazolidinyl urea | 39236-46-9 | 1 | 1 |

49 | tetrachlorosalicynanilide | 1154-59-2 | 1 | 0 |

50 | oxazolone | 1564-29-0 | 1 | 1 |

51 | acetyl-isovaleryl | 13706-86-0 | 1 | 1 |

52 | hydroxycitronellal | 107-75-5 | 1 | 1 |

53 | methylene diphenyl diisocyanate | 101-68-8 | 1 | 1 |

54 | dodecyl methanesulphonate | 51323-71-8 | 1 | 1 |

## Conclusions

## Acknowledgment

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**MDPI and ACS Style**

Fedorowicz, A.; Zheng, L.; Singh, H.; Demchuk, E.
QSAR Study of Skin Sensitization Using Local Lymph Node Assay Data. *Int. J. Mol. Sci.* **2004**, *5*, 56-66.
https://doi.org/10.3390/i5020056

**AMA Style**

Fedorowicz A, Zheng L, Singh H, Demchuk E.
QSAR Study of Skin Sensitization Using Local Lymph Node Assay Data. *International Journal of Molecular Sciences*. 2004; 5(2):56-66.
https://doi.org/10.3390/i5020056

**Chicago/Turabian Style**

Fedorowicz, Adam, Lingyi Zheng, Harshinder Singh, and Eugene Demchuk.
2004. "QSAR Study of Skin Sensitization Using Local Lymph Node Assay Data" *International Journal of Molecular Sciences* 5, no. 2: 56-66.
https://doi.org/10.3390/i5020056