Novel Screen Methodologies for Identification of New Microbial Metabolites
115
Finally, the microphysiometer is a silicon-based device which can be used to
detect and monitor the response of whole cells to a variety of chemical substances as well as facilitating the investigation of cell function and biochemistry. In
this instance the machine uses a light addressable potentiometric sensor (LAPS)
to measure the rate at which cells acidify their environment. The cells are
retained in a flow chamber in aqueous diffusive contact with the pH-sensitive
surface of a LAPS chip. Cellular acidification occurs mainly via glycolysis.
However, when there is a ligand-receptor interaction at the cell surface there are
substantial metabolic consequences in the cell which alter the acidification rate
and can be measured using this instrument 1-180].
For assays based around 96-well microtitre plate technology, the major
current trend in high throughput screening is to increase sample throughput in
the race to find new lead compounds. To this end robotic operation of screens
has become essential and several instrument companies (e.g. Robocon, Tomtek,
Tecan, Beckman/Wallac Oy) now offer complete or custom-built robotic systems to the pharmaceutical industry. At Xenova, we have developed our own
screening robot which has allowed us to retain flexibility of assay design and
given us a versatile system which is under in-house control and has a maximum
theoretical capacity of 1.2 million samples per year.
5.4 Rapid Delivery of New Drug Leads from Natural
Products Sources
In the increasingly competitive world of drug discovery it is essentially that, for
natural products screening, the available technology is amalgamated in a firmly
engineered process to minimise the time to lead candidate selection. At Xenova,
the average cycle time of our projects is one year with the first chemicals being
identified from approximated six months after the start of each screen.
In the next era of drug discovery, companies who wish to remain at the
forefront of screening technology will now need to develop radically different
approaches. Integration of robotics into screening programmes, advances in
bioinformatics, and re-engineering of drug discovery processes have all helped
to ensure maximum use of the microtitre plate. The next generation of assays
may be based on high density spotting techniques and paper technology,
advanced plastics research, inkjet methods, image analysis systems, biosensors
and nanotechnology among many others. For natural products discovery,
maximisation of secondary metabolite production and diversity, the integration
of chemical fingerprinting and other novel chemical technologies, and focusing
effort on assay preformance and data analysis facilitates the selection of quality
hits early in the process. Valuable natural products chemistry resources can then
be focused on fewer, better characterised samples, enabling identification of new,
biologically active, chemical entities which are currently beyond the capability
of chemical synthesis.
115
Finally, the microphysiometer is a silicon-based device which can be used to
detect and monitor the response of whole cells to a variety of chemical substances as well as facilitating the investigation of cell function and biochemistry. In
this instance the machine uses a light addressable potentiometric sensor (LAPS)
to measure the rate at which cells acidify their environment. The cells are
retained in a flow chamber in aqueous diffusive contact with the pH-sensitive
surface of a LAPS chip. Cellular acidification occurs mainly via glycolysis.
However, when there is a ligand-receptor interaction at the cell surface there are
substantial metabolic consequences in the cell which alter the acidification rate
and can be measured using this instrument 1-180].
For assays based around 96-well microtitre plate technology, the major
current trend in high throughput screening is to increase sample throughput in
the race to find new lead compounds. To this end robotic operation of screens
has become essential and several instrument companies (e.g. Robocon, Tomtek,
Tecan, Beckman/Wallac Oy) now offer complete or custom-built robotic systems to the pharmaceutical industry. At Xenova, we have developed our own
screening robot which has allowed us to retain flexibility of assay design and
given us a versatile system which is under in-house control and has a maximum
theoretical capacity of 1.2 million samples per year.
5.4 Rapid Delivery of New Drug Leads from Natural
Products Sources
In the increasingly competitive world of drug discovery it is essentially that, for
natural products screening, the available technology is amalgamated in a firmly
engineered process to minimise the time to lead candidate selection. At Xenova,
the average cycle time of our projects is one year with the first chemicals being
identified from approximated six months after the start of each screen.
In the next era of drug discovery, companies who wish to remain at the
forefront of screening technology will now need to develop radically different
approaches. Integration of robotics into screening programmes, advances in
bioinformatics, and re-engineering of drug discovery processes have all helped
to ensure maximum use of the microtitre plate. The next generation of assays
may be based on high density spotting techniques and paper technology,
advanced plastics research, inkjet methods, image analysis systems, biosensors
and nanotechnology among many others. For natural products discovery,
maximisation of secondary metabolite production and diversity, the integration
of chemical fingerprinting and other novel chemical technologies, and focusing
effort on assay preformance and data analysis facilitates the selection of quality
hits early in the process. Valuable natural products chemistry resources can then
be focused on fewer, better characterised samples, enabling identification of new,
biologically active, chemical entities which are currently beyond the capability
of chemical synthesis.