Molecular librarians create druglike collections


Finding biologically active small molecules with pharmaceutical potential is a bittersweet process. Now, a new approach to building libraries of diverse alkaloid-type structures has been developed by US chemists.

scaffold structures

The library is based on a selection of cut-down alkaloid-based molecular scaffolds

Jeffrey Aubé of the University of Kansas, Lawrence, and colleagues point out that many researchers have focused on natural products – and many pharmaceuticals have resulted from such approaches. Their success is attributed to the diversity of molecular skeletons gleaned from nature, as well as the higher number of sp3 carbon centres present. This endows derivatives with three-dimensional complexity and the chance to fit neatly into specific enzymes, receptors and other proteins involved in disease.

The Kansas team began with selected families of alkaloid natural products, extracted from plants that have a history in folk medicine, as well as molecules with identified medical, insecticidal and other bioactive properties. They began constructing the library based around cut down scaffolds of these alkaloids, using a wide-ranging approach to rapidly synthesise nearly 700 diverse compounds.

By starting with alkaloids, the team hoped that the ‘privileged structures’ of these often toxic but often medicinally active substances would help them home in on useful leads more quickly. The structural characteristics of those compounds nudged them in the right direction. ‘We did try to emphasise sp3 character by choice of the natural products,’ Aubé says. The team carried out a ‘Lipinski’s rule-of-five’ analysis to test how druglike the compounds are, taking in molecular weight, lipophilicity and hydrogen bonding potential. ‘We were a little surprised that the compounds were as highly Lipinski compliant as they turned out to be,’ he adds.

Natural products and their analogues are often too complex for commercially tenable synthesis. This streamlined approach allows Aubé’s team to generate diversity, while maintaining potential drug-like character but keeping the synthetic reaction schemes short. The team obtained up to 90% overall yields on 20mg product scales.

Paul Hergenrother of the University of Illinois recognises the work’s potential: ‘Alkaloids have such a diverse array of bioactivities, and can be active in the central nervous system,’ he says. ‘So, the creation of such a large number (and large diversity) of these compounds is clearly very important. These types of value-added products are likely to be markedly superior – in terms of hit potency and selectivity – to compounds in standard screening collections.’

 


Related Content

Chemists cull compounds using ‘intuition’

30 November 2012 Research

news image

Medicinal chemists apparently decided which fragments should be in their screening collection using surprisingly few paramete...

Opening up and sharing

18 April 2013 Comments

news image

Openly sharing information and research is changing chemistry, says Jean-Claude Bradley. Be first, or be forgotten

Most Read

Linguistic statistics enable synthetic prophetics

17 July 2014 Research

news image

A metric more commonly used by search engines to analyse language can now power organic chemistry retrosyntheses

Coffee cup confusion

20 July 2014 Research

news image

Scientists call for better labelling after research highlights inconsistencies in the chemical composition of a cup of coffee

Most Commented

Royal Society of Chemistry's flagship journal now free to access

16 July 2014 News and Analysis

news image

Chemical Science will follow gold open access model from January 2015 and waive author fees for two years

Science minister replaced in UK cabinet reshuffle

15 July 2014 News and Analysis

news image

Greg Clark replaces David Willetts as minister for science and universities