3D- QSAR Design of Novel Antiepileptic Sulfamides

GAVERNET LUCIANA; DOMINGUEZ CABRERA MARÍA J.; BRUNO BLANCH LUIS E.; ESTIU GUILLERMINA L.

Florida, EEUU

Simposio; 45th. Sanibel Symposium; 2005

Two million new cases of epilepsy occur in the world every year, affecting 1-2% of the world’s population. Antiepileptic Drug (AEDs) with better safety, less toxicity, and higher efficacy in difficult-to-control patients are urgently needed, as the available drugs are symptomatically effective in only 60-70% of patients.1 We report the design of new AED that interact with the neuronal voltage dependent sodium channel (VGSC) and belongs to the family of symmetric sulfamides. The design is based on a Comparative Molecular Field 3D-QSAR Analysis (CoMFA), a powerful approach to design new drug leads from the knowledge of small ligand structures. A chemical function-based pharmacophore model (Figure 1) has been derived from the comparison of 27 structures (training set), which included traditional a new generation AED. The “active” conformation of each molecule and the molecular alignment were determined on the basis of the electrostatic and structural properties of the pharmacophore.2The analysis provided statistically reliable models of good predictive power CoMFA r2= 0.961, q2= 0.755. The results obtained were graphically interpreted in terms of field contribution maps. Physicochemical determinants of binding, such as steric and electrostatic properties, were mapped onto the molecular structures of a set of AC (Figure 2). The results have been used to guide the rational design of new AE ligands. Five symmetric sulfamides were synthesized and evaluated in their AC activity. The 3D-QSAR models were particularly capable of predicting the activity of the designed compounds ( r2=0.946, q2=0.789). The structural and electronic analysis has been performed at a B3LYP/6-31G** level. The optimized structures were imported to Sybyl for CoMFA analysis. Molecules were superimposed using the fit atoms tool of Sybyl. For the QSAR analysis, atomic charges computed with the Gasteiger-Huckel method and with the Merz-Kollman approximation were compared.