During the XX century the dominant paradigm in creation of new drugs was based on suggestion about selectivity of action on a certain molecular target, which should lead to the normalization of pathological process. At the same time, the majority of known drugs interact with several or even many targets in the organism; however such action is mostly associated with unwanted adverse effects and toxicity. After the deciphering of human genome and first results achieved in postgenomic studies it became obvious that many diseases have a complex etiology, while drug action on a certain target often leads to activation/blockade of other elements in the appropriate regulatory network. As a consequence of negative feedbacks, expected pharmacotherapeutic action may be significantly decreased or even completely suppressed. The multitargeted drugs concept appears, according which such remedies due to the additive, synergistic or antagonistic action might have some advantages comparing to the monotargeted medicines. Discovery of new multitargeted drugs requires the solution of two tasks: (1) identification of targets which could be blocked or activated to achieve the desirable pharmacotherapeutic effect, and (2) finding of ligands that interact with the identified targets in a desirable mode. The first aim could be achieved by simulation of behavior in regulatory network blocking or activating certain nodes (targets) and their combinations. The second aim could be achieved either by prediction of biological activity spectra for molecules from different databases and selection of hits with the requested biological profiles, or by direct computer-aided design of multitargeted ligands. Possibilities and limitations of current bioinformatics and computer-aided drug design methods in discovery of particular molecular targets and their multiple ligands will be discussed.
Med. Chem. Res., 2010, 19 (S1), s30.