QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR). V. ANALYSIS OF THE TOXICITY OF ALIPHATIC ESTERS BY MEANS OF MOLECULAR COMPRESSIBILITY DESCRIPTORS
Vicenţiu Vlaia, Tudor Rareș Olariu, Lavinia Lia Vlaia, Marius Butur, Ciprian Ciubotariu, Mihai Medeleanu, Dan Ciubotariu · 2009
The present work represents an attempt to correlate toxicity of aliphatic esters using calculated molecular descriptors based on properties of the molecular van der Waals (vdW) space considered compressible in some extent. Assuming that a molecule can be compressed from the greatest sphere, corresponding to the vdW surface w S , to the smallest sphere, corresponding to the vdW volume, w V , we developed three i-dimensional structural parameters CiD, i=1,2,3, which are measures of compressibility in iD molecular vdW space. CiD compressibility measures of the vdW molecular space were tested with good results on a series of 56 aliphatic esters exhibiting toxicity to ciliate protozoan Tetrahymena pyriformis. A reduced series of 49 esters was obtained by outlier statistical analysis. The quality and the robustness of all the QSAR models were analyzed. For the QSAR model wherein C2D was used as predictor variable, the external cross-validation was performed. The goodness of fit and the predictive power of the QSAR models developed in this study show that accurately describing the toxicity of aliphatic esters with a single correlation equation is quite feasible if the physical meaning of the molecular descriptors is clear. Rezumat Aceasta lucrare reprezinta o tentativa de a corela toxicitatea esterilor alifatici utilizând descriptori moleculari calculaţi pe baza spaţiului molecular van der Waals (vdW), considerat, intr-o oarecare masura, compresibil. Presupunând ca o molecula poate fi comprimata de la sfera cea mai mare, care corespunde suprafeţei vdW, notata w S , la sfera cea mai mica, care corespunde volumul vdW, notat w V , am dezvoltat trei parametri structurali i-dimensionali, notaţi CiD, i=1,2,3, care sunt masuri ale compresibilitaţii in spaţiul molecular vdW i-dimensional. Masurile de compresibilitate ale spaţiului molecular FARMACIA, 2009, Vol. 57, 5 550 vdW, CiD, au fost testate cu bune rezultate pe o serie de 56 de esteri alifatici care isi manifesta toxicitatea asupra protozoarului ciliat Tetrahymena pyriformis. O serie redusa de 49 de esteri a fost obţinuta in urma analizei statistice a punctelor care se abat semnificativ de la dreapta de regresie (autlaier: „outliers”). Au fost analizate calitatea si robusteţea tuturor modelelor QSAR. Pentru modelul QSAR in care s-a utilizat variabila predictor C2D, a fost facuta validarea externa. Capacitatea de a reproduce datele experimentale (capacitatea de fitare) si puterea predictiva a modelelor QSAR obţinute in acest studiu demonstreaza ca descrierea cu acurateţe a toxicitaţii esterilor alifatici cu o singura (unica) ecuaţie corelaţionala este intr-adevar posibila daca semnificaţia fizica a descriptorilor moleculari este clara.