In silico drug design of benzothiadiazine derivatives interactingwith bilayer cell membranes

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and several selected derivatives designed in silico, with the basic components of cell membranes and solvents such as phospholipids, cholesterol and water. The analysis of the mutual microscopic interactions is of central importance to elucidate the local structure of benzothiadiazine as well as the mechanisms responsible for the distribution and access of benzothiadiazine to the interior of the cell. We have performed molecular dynamics simulations of benzothiadiazine and its derivatives embedded in a model zwitterionic bilayer membrane made by phospholipids dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol inside aqueous potassium chloride solution in order to systematically examine microscopic interactions of benzothiadiazine derivatives with the cell membrane at liquid-crystalline phase conditions. From data obtained through radial distribution functions, time dependent hydrogen-bond lengths and potentials of mean force based on reversible work calculations, we have observed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characterisitics can vary significantly: they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10-70 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of different characteristic lengths between 1.6 and 2.1 [A].