Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.
ChemMedChem. 2015 Oct 21;
Authors: Hung AW, Silvestre HL, Wen S, George GP, Boland J, Blundell TL, Ciulli A, Abell C
Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.
PMID: 26486566 [PubMed - as supplied by publisher]
Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases.
ChemMedChem. 2015 Feb;10(2):296-303
Authors: Scott DE, Coyne AG, Venkitaraman A, Blundell TL, Abell C, Hyvönen M
The development of small molecules that inhibit protein-protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole-based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP-dependent recombinase that plays a key role in the repair of double-strand DNA breaks. It both self-associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common "FxxA" tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small-molecule inhibitors that are approximately 500-fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2-derived Ac-FHTA-NH2 peptide and the self-association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small-molecular-weight fragments against this challenging target.
PMID: 25470112 [PubMed - indexed for MEDLINE]