The aim of pharmaceutical research in the present scenario is to modulate the targets
with the intention of evoking therapeutic benefits. The advent of DNA recombinant technology has
facilitated the preparation of almost any type of target in the purest form and in required amounts.
In parallel, combinatorial chemistry and high throughput organic synthetic approaches have
dramatically expanded the number of compounds that can be evaluated for biological activity. Both
these advances have paved the way to develop high throughput screening systems for evaluation of
millions of compounds against these targets in a rapid and efficient manner. However, overall return
on investment in these technologies has been meager and disappointing. Thus an alternate approach
which has the ability to potently and specifically modulate protein targets with small organic
molecules is a need of the hour. All these facts have contributed to the emergence of
multidimensional NMR as a gate way to drug design and development.
Fragment based drug design is the concept, where ligand binding site is dissected into different
regions and the binding of diverse compounds in individual sub sites are analyzed separately.
Fragments with fairly good affinity at all sub sites are collected and are interlinked in various
possible manners, intuitively to generate a new set of compounds. The affinity of these compounds
will be the sum of the affinity of individual fragments with additional gains due to entropy. In this
approach, ligand-target interaction is measured and characterized with at most accuracy and
precision as it caters valuable information in the areas like quantitative determination of binding
affinities of potential ligands, ligand binding site determination on protein, conformation
information of ligands and proteins and local flexibilities in the structure for complex and free
components. In addition NMR helps to determine ligand specificity and selectivity towards
different targets and also provide valuable hints to predict possible side effects and toxicological
outcomes at various levels. Another advantage of these techniques includes attaining capability to
eliminate the false positives. They are also useful in further optimization of the potential leads.
Drug receptor interaction is quantified based on various techniques through NOE, relaxation and
diffusion editing, isotope editing/ filtering, shapes strategy, HSQC strategy, etc. Fragment linking
and elaboration strategies are employed for linking the fragments together and design the new
molecules. Enormous number of compounds with high affinity towards several targets from FKBP
to Bcl-2 has been reported in the literature.
Based on the above facts, NMR can play a decisive role from in various stages of drug discovery
i.e., from structural elucidation to identifying medicinally valid drug candidates. This article is an
effort to throw a light on the basic principles involved in each and every technique of NMR, their
advantages and limitations, along with its applicability.
Keywords: NMR spectroscopy, drug discovery by NMR, multidimensional NMR, NMR techniques.
