Chapter 2: Transition Metal Systems

A growing number of therapeutic and diagnostic molecules contain transition metal centres while several important drug targets have one or more metal centres at their active site. Since a significant part of the discovery process involves computational modelling, there is a need to be able to handle TM systems theoretically. However, compared to purely organic systems, TM compounds present a number of challenges such as high and variable coordination numbers, inherently dynamic ligand substitution, and the electronic and spin-state effects arising from open-shell d configurations. Quantum chemistry (QC), most notably in the form of density functional theory (DFT), has matured to the stage where good quality first principles calculations on TM systems are feasible, and DFT can be applied, for example, to provide data for QSAR studies. However, the demands of high throughput screening, systematic conformational searching and long timescale molecular dynamics preclude DFT. Here, a much faster approach such as molecular mechanics (MM) is necessary and with care, and possibly some additional parameterisation, MM can be applied to a number of metal centres. For more complicated systems where conventional MM breaks down, extended models such as the author's ligand field molecular mechanics, can fill the gap.