DRUG DISCOVERY


An unusual technology marriage to assist drug discovery


Bill Hamilton of Prosarix and Steve Taylor of Enzagen explain how the combination of computational molecular modelling and biocatalysis can assist discovery scientists in their quest for new drug leads.


unprecedented rates to ensure survival in a rapidly changing market. Pressures are spiralling ever upwards as pharma and biotech compete and innovate to find and market the next big blockbuster. It is difficult to predict when the industry will stabilise, but certainly the drive to find novel compounds to feed hungry pipelines is on the rise.


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Historically, certain kinds of molecules such as natural products have greatly benefitted drug discovery and development. They still continue to be a source of inspiration for scientists today, and in modified or unmodified form have led to many successful drugs. Good examples of this are found in the statin drugs, used to lower cholesterol with spectacular clinical success. These drugs originated from the discovery of mevastatin produced by a Penicillium mold, and include Crestor and Lipitor, both of which are multi- billion dollar drugs. Whilst they are of synthetic design, both owe their origins to the natural product mevastatin (Fig 1). A striking feature of natural products at the molecular level is their abundance of ring structures, which appear in all shapes and sizes. They may be fused, bridged or in a spiro configuration, and may comprise carbon alone or, as heterocycles, include nitrogen


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mevastatin O


CO2H OH


F N NH O Lipitor® (atorvastatin)


Fig 1. Lipitor and Crestor: statins inspired by the natural product mevastatin. 32 sp2


November/December 2011 F O


he pharmaceutical industry continues to change and adapt at


and oxygen. Importantly, such features lend these molecules a certain rigidity and an ability to hold functional groups firmly in space relative to each other. The defined positioning of such groups frequently plays a central part in the biological performance of natural products, enabling a molecule to interact in various ways with a given protein, such as by hydrogen bonding or hydrophobic interactions, ultimately contributing to potency and, importantly, selectivity. This could help to explain the origins of a clear trend in the industry towards increasing complexity in many molecules that are coming out of discovery labs. This is seen by those who are close to the drug discovery coalface, as scientists seek to exploit the benefits of natural products where they can in their design processes.


Combining computational chem- istry and biocatalysis to discover new molecules


It is from these origins that Prosarix and Enzagen have combined their respective expertises in computational chemistry and biocatalysis to bring to market, under the name EnzacoresTM, new sets of molecules that assist medicinal chemists in probing three-dimensional space rapidly and efficiently. They have found utility in various aspects of the discovery process from finding


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CO2H OH


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new biological activity through to improving the performance of a promising molecule, optimising its physicochemical properties and, critically, enabling robust IP protection for the end user.


The general concept of Enzacore molecules is based on cyclic, and therefore reasonably rigid, non-aromatic structures, with multiple functional handles that are further ‘tuneable’ by the chemist (Fig 2). It goes without saying that chiral purity is a key property. It is in these respects that the similarity with, and inspiration from, natural products resides. Enzacore molecules can be viewed as prototypes for constructing molecules with natural-product-like features such as rigidity and ring systems, but by synthetic methods that are enabled by all the benefits that biocatalysis has to offer, particularly when it comes to installing the shape and purity of the molecule. Enzacores are constructed using key technologies from bioresolution with hydrolases through to asymmetric synthesis with oxidoreductases and transaminases, and enzymes are exploited for their exquisite ability to selectively transform molecules in a precise manner with accompanying chemical and regio control; and all under mild catalytic conditions. The green credentials of their synthesis thus represent a further attractive feature. In addition, the routes to the manufacture of Enzacores are designed around readily available starting materials assembled and manipulated in tractable, practical methodologies, developed from years of experience in large-scale biocatalytic manufacturing processes.


Crestor® (rosuvastatin) NN N S O O


Utility of Enzacore structures In the past few years, the scientific and patent literature has shown a significant increase in the presence of chiral cyclic molecules such as Enzacore structures in new drug leads, and it seems their benefits are evidently being appreciated. In some cases they form the central part of the molecule, projecting various binding groups into 3D space so that they can interact precisely with their biological target. In these examples the core structures are being used in a relatively simple ‘plug


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