Drug Targeting and Design
The most fundamental goal in drug design is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. The therapeutic response of a drug depends upon the interaction of drug molecules with cell on cell membrane related biological events at receptor sites in concentration dependent manner. Selective and effective localization of the pharmacologically-active moiety at pre-identified target(s) in therapeutic concentration, while restricting its access to non-target(s) normal cellular linings, thus minimizing toxic effects and maximizing the therapeutic index accounts from effective and efficient drug delivery.
Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Also, knowledge-based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target. Ideally, the computational method will be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized, saving enormous time and cost. The reality is that present computational methods are imperfect and provide, at best, only qualitatively accurate estimates of affinity. In practice it still takes several iterations of design, synthesis, and testing before an optimal drug is discovered. Computational methods have accelerated discovery by reducing the number of iterations required and have often provided novel structures.