Label-free high throughput biomolecular screening system and method

Abstract

A screening system and method are described herein which provide a unique and practical solution for enabling label-free high throughput screening (HTS) to aid in the discovery of new drugs. In one embodiment, the screening system enables direct binding assays to be performed in which a biomolecular interaction of a chemical compound (drug candidate) with a biomolecule (therapeutic target) can be detected using assay volumes and concentrations that are compatible with the current practices of HTS in the pharmaceutical industry. The screening system also enables the detection of bio-chemical interactions that occur in the wells of a microplate which incorporates biosensors and surface chemistry to immobilize the therapeutic target at the surface of the biosensors. The screening system also includes fluid handling and plate handling devices to help perform automated HTS assays.

1 . A screening system comprising a measurement chamber including a measurement nest used to position/reposition a microplate before biosensors that are incorporated within wells of the microplate are optically interrogated, and an automated instrument for athermalizing microplates, a plate handling system for moving the microplate into and out of the screening system, an automated instrument for positioning/repositioning microplates, an automated instrument for performing baseline and end-point measurements, and wherein the screening system is able to implement a plate ID and data processing solution that allows end-point assay data to be tracked and calculated to implement a measurement protocol that enables label-free detection of biomolecular interactions which take place on biosensors located in wells of at least one microplate, wherein the screening system exhibits a plate handling/data-point read cycle that has a duration that is shorter than the minimum required assay duration and the implementation of the above components allows plate multiplexing to achieve a target rate of 40,000 wells/8 hrs when the at least one microplates are 384 well microplates. 
     
     
         2 . The screening system of  claim 1 , further comprising a plurality of automated instruments for fluid dispensing and fluid mixing in the wells of the at least one microplate. 
     
     
         3 . The screening system of  claim 2 , further comprising a computer that operatively controls said plurality of automated instruments. 
     
     
         4 . The screening system of  claim 3 , wherein said computer executes a label-free screening protocol to interrogate the at least one microplate by combining baseline and end-point measurements with the movement of the at least one microplate into and out of the measurement nest in said measurement chamber to achieve the target rate of screening 40,000 wells/8 hrs when the at least one microplates are 384 well microplates. 
     
     
         5 . The screening system of  claim 3 , wherein said computer executes an assay mode to obtain real time bio-chemical interaction data by screening said at least one microplate. 
     
     
         6 . The screening system of  claim 1 , wherein said at least one microplate each has fiducial markings thereon which are used to properly position/reposition said at least one microplate in said measurement chamber. 
     
     
         7 . The screening system of  claim 1 , further comprises a device that interacts with an external high throughput system line, said device including:
 a rotating arm;   a drawer;   a lifter;   a gripper;   a carriage;   a rail; or   a conveyor.   
     
     
         8 . The screening system of  claim 1 , wherein said automated instrument for handling microplates is:
 a rotating arm;   a plate carriage;   a gripper;   a lifter; and/or   a conveyor system.   
     
     
         9 . The screening system of  claim 1 , wherein said automated instrument for positioning/repositioning microplates is:
 a microplate handling module; and/or   an X-Y support stage.   
     
     
         10 . The screening system of  claim 1 , wherein said automated instrument for performing end-point measurements is an optical interrogation system. 
     
     
         11 . A method for performing a label-free assay, said method comprising the steps of:
 athermalizing a plurality of microplates;   moving, in accordance with a measurement protocol, at least one of the microplates into and out of a measurement chamber;   positioning/repositioning, in accordance with the measurement protocol, at least one of the microplates within the measurement chamber;   performing base-line measurements and end-point measurements, in accordance with the measurement protocol, on at least one of the microplates to enable label-free detection of biomolecular interactions that take place on biosensors within the wells of said at least one of the microplates; and   processing plate ID and data so as to track and calculate end-point measurement data,   wherein the screening system exhibits a plate handling/data-point read cycle that has a duration that is shorter than the minimum required assay duration and the implementation of the above steps allows plate multiplexing to achieve a target rate of 40,000 wells/8 hrs when the at least one microplates are 384 well microplates.   
     
     
         12 . The method of  claim 11 , wherein said measurement protocol is a screening protocol which enables the interrogation of a plurality of microplates by combining baseline and endpoint measurements with the movement of the microplates into and out of the screening system to achieve the target rate of screening 40,000 wells/8 hrs when the at least one microplates are 384 well microplates. 
     
     
         13 . The method of  claim 11 , wherein said measurement protocol is an assay mode to obtain real time bio-chemical interaction data by screening said at least one microplate. 
     
     
         14 . A screening system comprising:
 a measurement chamber for maintaining a predetermined temperature around a microplate and having a measurement nest used to position the microplate before optical biosensors that are incorporated within the walls of the microplate are optically interrogated;   an automated instrument in the form of athermalization buffer for receiving, storing and maintaining a predetermined temperature around one or more microplates;   an automated instrument for handling microplates in the form of an interface device for moving microplates from the athermalization buffer to the measurement chamber and which functions as an interface with external equipment;   an automated instrument for positioning microplates;   an automated instrument for performing baseline and end-point measurements; and   a computer for controlling said plurality of automated instruments,   wherein the system has a plate-handling/data-point read cycle that has a duration that is shorter than the minimum required assay duration,   wherein the system is arranged for processing a plate identification and data so as to track and calculate end-point assay data,   such that the system is able to implement by plate multiplexing a measurement protocol that enables label-free detection of biomolecular interactions which take place on optical biosensors located in wells of at least one microplate, with a throughput rate of at least 40,000 wells/8 hours.   
     
     
         15 . The screening system of  claim 14 , further comprising a plurality of automated instruments which are together adapted for dispensing fluid in the wells of the at least one microplate and mixing said fluid. 
     
     
         16 . The screening system of  claim 15 , wherein said computer is adapted to execute a label-free high throughput screening protocol to interrogate the at least one microplate by combining baseline and end-point assays with the movement of the at least one microplate into and out of a measurement nest in said measurement chamber. 
     
     
         17 . The screening system of  claim 15 , wherein said computer is adapted to execute an assay development protocol to obtain real time bio-chemical interaction data by screening said at least one microplate. 
     
     
         18 . The screening system of  claim 14 , wherein said at least one microplate each has fiducial markings thereon for positioning said at least one microplate in said measurement chamber. 
     
     
         19 . The screening system of  claim 14 , said interface device including:
 a rotating arm; or   a drawer; or   a lifter; or   a gripper; or   a carriage; or   a rail; or   a conveyor.   
     
     
         20 . The screening system of  claim 14 , wherein said automated instrument for positioning microplates includes at least one of:
 a microplate handling module for handling microplates; and   an X-Y support stage.   
     
     
         21 . The screening system of  claim 14 , wherein said automated instrument for performing baseline and end-point measurements is an optical interrogation system. 
     
     
         22 . A method for performing a label-free assay, said method comprising the steps of:
 athermalizing a plurality of microplates by receiving, storing and maintaining a predetermined temperature around the microplates in an athermalization buffer;   moving at least one of the microplates into and out of a measurement chamber;   positioning at least one of the microplates within the measurement chamber;   performing base-line measurements and end-point measurements on at least one of the microplates to enable label-free detection of biomolecular interactions that take place on optical biosensors within the wells of said at least one of the microplates,   wherein the method comprises processing plate identification and data so as to track and calculate end-point assay data,   wherein the plate-handling/data-point read cycle that has a duration that is shorter than the minimum required assay duration,   and wherein by plate multiplexing the method provides a throughput rate of at least 40,000 wells/8 hours.