ATP synthase is the primary means of cellular energy production in all animals, plants, and almost all microorganisms. It is well known that failure of the ATP synthase complex can result in a wide variety of diseases and that this enzyme may also be used as a therapeutic drug target in the treatment of many diseases. Creative Biolabs has focused on the development of new inhibitors of ATP synthase for many years and has established excellent platforms for drug development.
ATP synthase is a general term for an enzyme that can synthesize adenosine triphosphate from adenosine diphosphate and inorganic phosphate. It is one of the oldest and most highly conserved enzymes. ATP synthase molecules are membrane-bound transporters that couple ion movement through a membrane with the synthesis or hydrolysis of an ATP nucleotide. The simplest F1Fo-ATP synthase contains eight different subunits, namely α3β3γδεab2c10. The total molecular mass is ~530 kDa. F1 corresponds to α3β3γδε and Fo to ab2c10. ATP hydrolysis and synthesis occur on three catalytic sites in the F1 sector, whereas proton transport occurs through the membrane-embedded Fo sector.
Fig.1 Structure of Escherichia coli ATP synthase. (Ahmad, 2010)
The importance of ATP synthase as a promising target for drug development is evident from the fact that many antibiotics such as efrapeptins, aurovertins, and oligomycins inhibit its function. Antibiotics efrapeptins and aurovertins inhibit both synthesis and hydrolysis of ATP by ATP synthase. The efrapeptins bind to ATP synthase at a site extending from the rotor, across the central cavity of the enzyme, into the specific β-subunit catalytic site. This binding prevents the closure of the β subunit during the rotary cycle. Aurovertins are known to bind and inhibit mitochondrial ATPase, thereby uncoupling oxidative phosphorylation. Two molecules of aurovertin bind simultaneously to the cleft between nucleotide-binding and C-terminal domain of two β subunit domains. Oligomycin is a potent inhibitor of ATP synthase by binding in the Fo sector and blocking proton conduction. A study suggested that interaction with components of mitochondrial pathways by oligomycin may lead to apoptosis of select cells.
To reach the goal of novel antibiotics, whether against validated or novel bacterial targets, Creative Biolabs is exploiting structure-based design tools as an effective route for drug discovery. The structure-based design allows the prioritization of chemical synthesis, with medicinal chemistry focusing on key synthetic stratagems in an efficient manner. There are three main methods used to identify new ligands based on structural information.
This approach takes a known inhibitor and structurally modifies it to give more potent inhibitors.
This approach involves the de novo design of inhibitor scaffolds. For example, fragments are positioned in chosen sites in the ATP synthase and then joined to create full molecules. These molecules are scored and ranked for factors such as their predicted binding affinity.
In virtual screening, rapid docking algorithms are used to search databases of commercially available compounds in order to identify novel molecules predicted to bind to the chosen protein target.
Creative Biolabs’ new antibiotic development services offer numerous options to meet a variety of research needs. Our team provides you with outstanding support and meets your specific needs with a professional technology platform. If you are interested in our services, please contact us for more details.
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