ISSN:
1573-4951
Keywords:
Structure-based drug design
;
De novo molecular design
;
Combinatorial chemistry
;
Synthetic constraint
;
Thrombin inhibitors
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008094712424
Permalink
