Structure-Activity Relationship Studies in Drug Development by NMR Spectroscopy

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Drug discovery is still a process which involves screening of a large number of chemical compounds against a defined biological target. However, this approach is now being gradually replaced by more ...
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NMR-A Gate Way to Drug Discovery

Pp. 1-35 (35)

Raghu Prasad Mailavaram and Murty Devarakonda

Abstract

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.

Affiliation:

Department of Pharmaceutical Chemistry, Shri Vishnu College of Pharmacy [Affiliated to Andhra University, Visakhapatnam], Padmabhushan Dr. B. V Raju Foundation and Sri Vishnu Educational Society, Vishnupur, Bhimavaram, West Godavari District, Andhra Pradesh, 534202-India