Stephen Clinton Young

PRO_SELECT: Combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritised for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

Targeted molecular diversity in drug discovery: Integration of structure-based design and combinatorial chemistry

A powerful new approach emerging in drug discovery research combines computational screening of virtual combinatorial libraries against a therapeutic target and targeted combinatorial library synthesis. This new approach includes positive features from both structure-based design and combinatorial chemistry. It has the potential of producing combinatorial libraries with a high hit rate, and hence accelerates the generation of quality lead compounds. The effectiveness of this novel approach has been shown by the design and synthesis of potent inhibitors for serine and aspartyl proteases.

The design of phenylglycine containing benzamidine carboxamides as potent and selective inhibitors of factor Xa

Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa.