Rational drug design: structure dictates function in amide derivatives

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  • Published: Jun 15, 2016
  • Author: Ryan De Vooght-Johnson
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The long road to approval

Every year, thousands of new compounds are synthesised, many of them potential drug candidates, but the development of a drug is a long and expensive process. Taking a drug from idea to the launch of a finished product can take 15 years and cost millions, if not billions, of dollars.

Every year, thousands of new compounds are synthesised, many of them potential drug candidates, but the development of a drug is a long and expensive process. Taking a drug from idea to the launch of a finished product can take 15 years and cost millions, if not billions, of dollars. On average, just one in every 5000 compounds will become an approved drug.

This process often begins by evaluating the biological activity of large sets of chemicals. To more efficiently identify potential drugs, it is important to understand the relationship between a compound’s structure and chemical properties and its biological activity.

Technology can help to speed up this process. Computers can help to not only choose the best drug candidates, but also predict their mode of action and facilitate their development. This is called computer-aided drug discovery, and is being increasingly used by regulatory agencies and pharmaceutical companies. Quantitative structure–activity relationship (QSAR) analysis, for example, is a popular computer-aided tool for drug discovery and can be used to predict the activity of compounds before they are even synthesised.

QSAR predicts activity based on structure. A molecule’s activity heavily depends on how it interacts with its environment and – when it comes to a drug – its ability to form chemical bonds to a receptor. The structural features of the drug, such as the chemical properties of its side chains, play a crucial role in these interactions.

Amazing amides

In a study recently published in the Journal of Chemometrics, Serbian researchers analysed the interactions of amide-based compounds. Amides – organic compounds derived from ammonia – and their derivatives are a popular group of drug candidates. Owing to their wide range of biological properties, they can act as antibiotics, painkillers, anticonvulsants, chemotherapy agents and antidepressants.

As well as binding to large molecules in the body (such as protein receptors), amides form secondary bonds with other amide groups and other functional groups present in the environment. To understand the structural basis of these interactions, the researchers used chromatographic and UV spectroscopy methods as the interactions the compounds make during these forms of analysis are similar to those it can establish in the body.

The future of drug discovery?

To understand the effects of chemical structure and solvent on the interactions, they tested a range of amide derivatives (specifically N-(4-phenylsubstituted) cyanoacetamides) using reversed-phase thin-layer chromatography and UV spectroscopy in the presence of several organic solvents, including methanol, ethanol, propanol and butanol.

The results, such as retention time and absorption frequency, were analysed using multivariate statistical methods to identify links between solvent properties, chemical characteristics and interactions. The researchers used several methods including cluster analysis (a method of grouping similar variables) and principal component analysis (which emphasises variation and brings out the patterns in data).

The results from chromatography suggested that the interactions of the compounds are determined by the polarity and proton donor ability of the solvents, while spectrophotometry revealed that the solvent’s ability to form hydrogen bonds also has an impact on cyanoacetamide interactions. In terms of structure, the orientation of the ring substituent (R, which is attached to a benzene ring on the molecule) was found to be the most important.

Lead researcher Gyongyi Vastag, from Serbia’s University of Novi Sad, summarises the findings: “The multivariate methods were able to detect the effects of both the substituent and solvent properties on the future interaction ability of N-(4-phenylsubstituted) cyanoacetamides.” More broadly speaking, these results show that multivariate analysis is useful to predict the effects of chemical and structural properties on the interactions and activity of drug candidates, and could form a larger part of the drug development process in the future.

Related Links

J. Chemometrics, 2016, 30: 210–216. Vastag et al., Structure-interaction relationship study of N-(4-phenylsubstituted) cyanoacetamides by multivariate methods.

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Article by Ryan De Vooght-Johnson

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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