[Methods of computer-assisted molecular modeling].

Abstract

We present an overview on modern computer methods of molecular modelling. After treating three main steps of drug evaluation, namely target identification, lead identification and lead optimisation, we shortly discuss molecular graphics, molecular mechanics, molecular orbital and molecular dynamics methods. These are suitable for the more-or-less adequate modelling of real molecular processes both at the microscopic and the macroscopic levels. Molecular graphics provides beautiful pictures for the specialist that allow inspection and manipulation of detailed molecular models. An especially useful tool for the visualisation of molecular entities is the display of various properties on the molecular surface that allows rapid recognition of important relationships. Molecular mechanics is able to predict properties (e.g. geometric parameters, conformer stability) of several classes of molecules with an accuracy close to the experimental one, therefore it plays an important role in complementing molecular graphics. The performance of molecular orbital methods increased considerably in the last decade thus we can calculate parameters for isolated or interacting molecules that are not easily amenable to experiment (e.g. structure and energetics of unstable species or activation energies of elementary processes). Computer simulation methods provide a link between gas-phase models of microscopic structures or processes and macroscopic properties or events that may be derived from the former. Thus, it became possible to apply computerised methods for an adequate simulation of important events, like chemical and biochemical reactions, drug-target interactions, drug delivery and the similar that determine drug action. It is stressed that the hardware and software for computer-aided molecular modelling may not be absent from the arsenal of a drug designer.