Water Solvent and Local Anesthetics: A Computational Study R. C. BERNARDI, 1 D. E. B. GOMES, 2 P. G. PASCUTTI, 2 A. S. ITO, 3 C. A. TAFT, 1 A. T. OTA 4 1 Departamento de Fı ´sica Aplicada, Centro Brasileiro de Pesquisas Fı ´sicas, CBPF, Rio de Janeiro, Brazil 2 Laborato ´rio de Modelagem e Dina ˆmica Molecular, Instituto de Biofı ´sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil 3 Departamento de Fı ´sica e Matema ´tica, Faculdade de Filosofia, Cie ˆncias e Letras de Ribeira ˜o Preto, Universidade de Sa ˜o Paulo, Brazil 4 Departamento de Fı ´sica, Centro de Cie ˆncias Exatas, Universidade Estadual de Londrina, Brazil Received 1 November 2006; accepted 12 December 2006 Published online 2 February 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/qua.21300 ABSTRACT: There are various experimental studies regarding the toxicity and the time of action of local anesthetics, which contain general insights about their pharmacological and physicochemical properties. Although a detailed microscopic analysis of the local anesthetics would contribute to understanding these properties, there are relatively few theoretical studies about these molecules. In this article, we present the results from calculations performed for three local anesthetics: tetracaine, procaine, and lidocaine, both in their charged and uncharged forms, in aqueous environment. We have used the density functional theory and molecular dynamics simulations to study the structural characteristics of these compounds. The radial distribution function g(r) was used to examine the structure of water molecules surrounding different regions of the local anesthetics. We demonstrated the nonhomogeneous character of the anesthetics with respect to their affinity to water solvent molecules as well as the modifications in their affinity to water caused by changes in their charge state. We also observed that the biological potency of the anesthetics is more related to the behavior of specific groups within the molecule, which are responsible for the interaction with the lipid phase of membranes, rather than the general properties of the molecule as a whole. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem 107: 1642–1649, 2007 Key words: density functional theory; molecular dynamics; radial distribution function; local anesthetics; hydrophobicity Correspondence to: A. T. Ota; e-mail: tsutomu@uel.br Contract grant sponsor: FAPESP. Contract grant sponsor: CAPES. Contract grant sponsor: CNPq. International Journal of Quantum Chemistry, Vol 107, 1642–1649 (2007) © 2007 Wiley Periodicals, Inc.