Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.
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.
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK.|Experimental Therapeutic Centre, A-STAR, 11 Biopolis Way, Singapore, 138667, Singapore.
Alvin W
AW
Hung
Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, CB2 1GA, UK.
H Leonardo
HL
Silvestre
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK.
Shijun
S
Wen
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK.
Guillaume P C
GP
George
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK.
Jennifer
J
Boland
Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge, CB2 1GA, UK.
Tom L
TL
Blundell
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK.|Division of Biological Chemistry & Drug Discovery, College of Life Sciences, James Black Centre, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
Alessio
A
Ciulli
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB2 1EW, UK. ca26@cam.ac.uk.
Chris
C
Abell
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D010453:Peptide Synthases; C022318:pantothenate synthetase
Mycobacterium tuberculosis; drug design; fragment-based screening; group efficiency; pantothenate synthetase