Efficient discovery of anti-inflammatory small-molecule combinations using evolutionary computing.
The control of biochemical fluxes is distributed, and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multiobjective evolutionary algorithm to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1β expression. The evolutionary algorithm converged on excellent solutions within 11 generations, during which we studied just 550 combinations out of the potential search space of ~9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the evolutionary algorithm were then optimized pairwise. A p38 MAPK inhibitor together with either an inhibitor of IκB kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1β expression. Evolutionary searches provide a powerful and general approach to the discovery of new combinations of pharmacological agents with therapeutic indices potentially greater than those of single drugs.
Doctoral Training Centre, Integrative Systems Biology Molecules to Life, Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester, UK.
Ben G
BG
Small
Barry W
BW
McColl
Richard
R
Allmendinger
Jürgen
J
Pahle
Gloria
G
López-Castejón
Nancy J
NJ
Rothwell
Joshua
J
Knowles
Pedro
P
Mendes
David
D
Brough
Douglas B
DB
Kell
D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D054852:Small Molecule Libraries