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 occurr 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 and a plurality of automated instruments for athermalizing microplates, handling microplates, positioning/repositioning microplates and performing end-point measurements 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.  
   
   
       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 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.  
   
   
       5 . The screening system of  claim 3 , wherein said computer executes an assay development protocol to perform semi-continuous measurements on 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 each biosensor has a signal area and a reference area.  
   
   
       9 . The screening system of  claim 1 , wherein each biosensor has surface attachment chemistry on a surface thereof to bind a therapeutic target.  
   
   
       10 . The screening system of  claim 1 , wherein each biosensor is a resonant waveguide grating (RWG) biosensor.  
   
   
       11 . The screening system of  claim 1 , wherein said automated instrument for athermalizing microplates is an athermalization buffer.  
   
   
       12 . 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.    
   
   
       13 . 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.    
   
   
       14 . The screening system of  claim 1 , wherein said automated instrument for performing end-point measurements is an optical interrogation system.  
   
   
       15 . 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.    
   
   
       16 . The method of  claim 15 , wherein said measurement protocol is a high throughput 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.  
   
   
       17 . The method of  claim 15 , wherein said measurement protocol is an assay development protocol which is used to perform semi-continuous measurements on said at least one of the microplates.  
   
   
       18 . A screening system comprising a measurement chamber and a computer that controls a plurality of automated instruments for athermalizing microplates, handling microplates, dispensing fluid in microplates, mixing fluid in microplates, positioning/repositioning microplates and performing end-point measurements 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.  
   
   
       19 . The screening system of  claim 18 , wherein said computer executes a label-free high throughput screening protocol to interrogate a plurality of the microplates by combining baseline and end-point assays with the movement of the microplates into and out of a measurement nest in said measurement chamber.  
   
   
       20 . The screening system of  claim 17 , wherein said computer executes an assay development protocol to perform semi-continuous measurements on said at least one of the microplates.  
   
   
       21 . A screening system that includes a measurement chamber/optical interrogation system and automated instruments that function together to perform end-point assays, with microplate moving in/out, and with microplate multiplexing to execute a label-free high throughput screening protocol in order detect label-free biomolecular interactions which take place on biosensors located in wells of at least one microplate.  
   
   
       22 . The screening system of  claim 21 , wherein each biosensor is a resonant waveguide grating (RWG) biosensor.  
   
   
       23 . A screening system that includes a measurement chamber/optical interrogation system and automated instruments that are capable of operating in an assay development mode and screening a predetermined number of label-free biosensors located within wells of a microplate with a coefficient of variance less than 7.9%.  
   
   
       24 . The screening system of  claim 23 , wherein each biosensor is a resonant waveguide grating (RWG) biosensor.