On the Paradigm Shift Towards Multitarget Selective Drug Design

Nigus      Dessalew; Workalemahu      Mikre

Abstract

Modern drug discovery has contributed much to the progress of medicine and well being of societies during the past century. Generally, a disease relevant macromolecule is studied first in vitro, in cells and in whole organisms, and evaluated as a potential drug target for a specific therapeutic intervention. Medicinal chemistry projects then commence by the search and identification of a binding partner for the single macromolecular target. This one-drug one-target design strategy is what has been in use for several decades and is widely pursued both in the academia and in the pharmaceutical industry. However, many debilitating disorders such as cancers, cardiovascular diseases, dementias, depression, to name few, basically result from multiple molecular abnormalities, not from a single defect. Moreover, systems biology has revealed that human cells and tissues are composed of complex, networked systems with redundant, convergent and divergent signaling pathways. And hence, it is increasingly being recognized that a balanced modulation of the several but relevant and inter connected targets can provide a superior therapeutic and side effect profile of drugs compared to the more conventional one-drug one-target one-disease practice. Although the currently available drugs are inherently multiple acting, the design of multi-target selective drugs is just a recent trend and is beginning to be appreciated by the scientific community. The success of this promising drug-design paradigm will depend on advances in the identification of the correct and relevant multiple targets and their binding partners. This manuscript reviews the emerging concepts of attacking multiple targets through a deliberate design of agents which could bind with a selected number of several proteins relevant in a given disease. The current knowledge and tools for the rational design of a multitarget selective ligand is reviewed and the challenges, limitations and outlook of such novel ligand design strategy is presented.

Keywords: Drug design, drug selectivity, pharmacophore, QSAR, multiple target

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