ABSTRACT
How, then, does one achieve specificity? Specificity is fundamentally molecular information. One builds in specificity by understanding the “rules of recognition” between one molecule and another through the use of hydrogen bonds, ionic interactions, hydrophobic interactions, and, of course, the overall three-dimensional structure. If one analyzes our success in drug discovery so far, one can derive a “specificity scale” (shown in Fig. 8) relating the complexity of molecular targets to the amount of information one can incorporate into a potential inhibitor or binding agent. We have been most successful with enzymes in terms of specificity. On the other hand, transcription complexes, including transcription factors, activators, repressers, often seven to nine components along with DNA in the milieu, represent a much more daunting challenge. They may very well represent the most complicated state so far for targets of drug discovery. In the middle tier are nucleic acids, antibodies, dimeric domain recognition kinds of targets, signaling proteins, and receptors. If one reviews the past decade of drug discovery progress, it parallels the specificity scale.
