Current Topics in Medicinal Chemistry - Volume 9, Issue 18, 2009

In the last decade fragment-based methods have become rapidly established in drug discovery and although it is too early for these approaches to have yielded a marketed drug, they have resulted in a significant number of drug candidates entering clinical trials and many more in pre-clinical development. Fragment-based methods were first successfully applied, further explored and rapidly adopted in the biotechnology and p Read More

The history of fragment-based drug discovery, with an emphasis on crystallographic methods, is sketched, illuminating various contributions, including our own, which preceded the industrial development of the method. Subsequently, the creation of the BMSC fragment cocktails library is described. The BMSC collection currently comprises 68 cocktails of 10 compounds that are shape-wise diverse. The utility of these cockt Read More

Diseases of the central nervous system are among the most devastating to patients and their families. Despite this, treatments for these diseases have lagged behind other therapeutic areas. Although social and economic factors may be partly responsible for the paucity of therapeutic agents, a particularly daunting challenge for CNS drug discovery is the need for compounds to cross the blood brain barrier. Recent analyses of Read More

Multiple ligand efficient fragment inhibitors of protein kinase B were identified through a combined in silico compound screen and high-throughput crystallographic analysis of protein-ligand structures. A well-validated apo-PKBPKA chimeric protein provided a convenient platform for high-throughput crystallography by soaking of inhibitors, and a method for the determination of PKB-ligand structures was developed to supp Read More

Fragment-based drug discovery (FBDD) is an important new tool to understand the molecule basis of ligandbiological target interactions. By combining optimal fragments, it is often possible to construct larger molecular weight compounds that have greater potency in a shorter period of time than can been achieved by the initial screening of larger molecular weight compound libraries. Alternatively, if screening of more t Read More

The transition from high throughput screening of collections of drug-like compounds to screening of fragment libraries via lower throughput methods with high sensitivity has revolutionized early drug discovery. It is highlighting the need for sensitive biophysical techniques for interaction analysis rather than high throughput methods. Biosensors with SPR detection are well suited for this novel scenario. In less than 20 year Read More

Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with KD valu Read More