Chemical structure:Layout 1

In the pharmaceutical world, scientists routinely use 2D structural likeness to indicate similar biological action. 2D ‘atom and bond’ representation such as those shown in Figure 1 are, after all, the de facto language of chemistry. So why question the authority of this representation after applying it for so long on all aspects of drug discovery from activity enhancement to toxicity and from patent application to safety issues? The reason is simple – it has a serious limitation that inhibits our ability to discover, protect and bring to market new drugs. That limitation is familiar to most chemists. We have known for many years that very different structures can act at the same biological target to effect the same biological action. The obvious conclusion must be that chemical structure – atoms linked by bonds – is not what is recognised by a biological target. Molecule A and molecule B in Figure 1 bear no structural relationship to one other and yet molecule B mimics molecule A – both are able to occupy the same site on a common target (see Figure 4). The corollary is also often true; very closely related derivative structures regularly exhibit very diverse activities at a given target. This inability of 2D structure to describe a compound’s activity has profound consequences. Chemists are routinely required to make ‘chemotype jumps’ to move from one chemical class, all members of which have one or more common structural features, to another. Such chemotype jumps are vital if structures are to be novel and patentable, if pre-clinical ADME (absorption, distribution, metabolism, and excretion), safety and By Dr Andy Vinter, Dr Steve Gardner and Dr Sally Rose Overcoming the limitations of chemical structure