Binding constants of neuraminidase inhibitors: An investigation of the linear interaction energy method

The linear interaction energy (LIE) method has been applied to the calculat ion of the binding free energies of 15 inhibitors of the enzyme neuraminida se. This is a particularly challenging system for this methodology since th e protein conformation and the number of tightly bound water molecules in t he active site are known to change for different inhibitors. It is not clea r that the basic LIE method will calculate the contributions to the binding free energies arising from these effects correctly. Application of the bas ic LIE equation yielded an rms error with respect to experiment of 1.51 kca l mol(-1) for the free energies of binding. To determine whether it is appr opriate to include extra terms in the LIE equation, a detailed statistical analysis was undertaken. Multiple linear regression (MLR) is often used to determine the significance of terms in a fitting equation; this method is i nappropriate for the current system owing to the highly correlated nature o f the descriptor variables. Use of MLR in other applications of the LIE equ ation is therefore not recommended without a correlation analysis being per formed first;. Here factor analysis was used to determine the number of use ful dimensions contained within the data and, hence, the maximum number of variables to be considered when specifying a model or equation. Biased fitt ing methods using orthogonalized components were then used to generate the most predictive model. The final model gave a q(2) of 0.74 and contained va n der Waals and electrostatic energy terms. This result was obtained withou t recourse to prior knowledge and was based solely on the information conte nt of the data.