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Priori%zing Scaffolds for Hit Selec%on 
    in High Throughput Screening 
              Programs  
         Rajarshi Guha, Dac‐Trung Nguyen 
          NIH Chemical Genomics Center 

        6th Indo‐US Workshop on Mathema%cal Chemistry 
                     8th – 10th January, 2010 
Outline 
•  HTS and qHTS at the NCGC 
•  Hit selec%on & cherry picks 
•  The fragment based approach 
NIH Chemical Genomics Center 
Assay development                                               Compound 
and op2miza2on                                                  Op2miza2on 

                                  Small Molecules 


                           Biology            Chemistry 

                                      NCGC 

                          Informa%cs            ACOM 

                                  Genome wide RNAi 

SAR analysis, method &                                  Automa2on, Compound 
tool development                                        management 
High Throughput Screening 
•  Assay thousands to 
   hundreds of thousands 
   of compounds 
   –  Biochemical, gene%c, 
      pharmacological assays 
•  Rapidly iden%fy novel 
   modulators of biological 
   systems 
•  Lots of raw data – 
   automated analy%cs are 
   essen%al 
Hun%ng for Leads 

           Target              Lead             Lead               Clinical 
        Iden%fica%on          Discovery       Op%miza%on          Development 




HTS 
                              Primary 
                                                                    Confirma%on 
  •  Sensi%vity              Screening    •  Select subset 
  •  Scaling           •  Fluorescence       to follow up       •  Counter 
                       •  High Content    •  Diversity             screen 
                                                                •  Explore SAR 
          Assay 
                                              Cherry Picking 
       Op%miza%on 
High Throughput Screening 
•  Given a screen, we 
   must iden%fy ac%ve 
   compounds and 
   confirm their ac%vity 
•  Most HTS campaigns 
   are run at a single 
   concentra%on 
                                          Negative
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                                                                                                                 Plate Number
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS
Prioritizing Scaffolds for Hit Selection in HTS

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Prioritizing Scaffolds for Hit Selection in HTS

  • 1. Priori%zing Scaffolds for Hit Selec%on  in High Throughput Screening  Programs   Rajarshi Guha, Dac‐Trung Nguyen  NIH Chemical Genomics Center   6th Indo‐US Workshop on Mathema%cal Chemistry  8th – 10th January, 2010 
  • 3. NIH Chemical Genomics Center  Assay development  Compound  and op2miza2on  Op2miza2on  Small Molecules  Biology  Chemistry  NCGC  Informa%cs  ACOM  Genome wide RNAi  SAR analysis, method &  Automa2on, Compound  tool development  management 
  • 4. High Throughput Screening  •  Assay thousands to  hundreds of thousands  of compounds  –  Biochemical, gene%c,  pharmacological assays  •  Rapidly iden%fy novel  modulators of biological  systems  •  Lots of raw data –  automated analy%cs are  essen%al 
  • 5. Hun%ng for Leads  Target  Lead  Lead  Clinical  Iden%fica%on  Discovery  Op%miza%on  Development  HTS  Primary  Confirma%on  •  Sensi%vity  Screening  •  Select subset  •  Scaling  •  Fluorescence  to follow up  •  Counter  •  High Content  •  Diversity  screen  •  Explore SAR  Assay  Cherry Picking  Op%miza%on 
  • 6. High Throughput Screening  •  Given a screen, we  must iden%fy ac%ve  compounds and  confirm their ac%vity  •  Most HTS campaigns  are run at a single  concentra%on  Negative 150 Positive ! ! ! ! ! ! ! Sample ! ! ! ! ! ! ! !!! ! ! ! ! ! ! ! !! ! ! ! ! ! !! ! ! ! ! ! !! ! ! ! ! !! !! ! ! ! ! ! !! ! ! !! ! !! ! !! ! ! ! ! ! ! ! ! ! !! !! ! ! ! ! !! ! ! ! ! ! ! ! !! ! !! ! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! !! ! ! ! !! ! ! ! ! !! ! !! ! ! !! !! ! ! ! ! ! ! ! ! ! !! ! ! ! ! !! ! ! ! ! ! !! ! !! ! !! ! ! ! !! !! ! !! ! !! ! !! ! !! ! ! ! ! ! ! ! !! ! ! ! ! !! ! ! ! ! !! ! !! ! !! ! ! ! !! !! !! ! !! !! ! ! ! !! !! ! ! ! ! ! ! ! !! ! ! ! ! ! !! !! ! ! ! ! ! ! ! ! ! !! ! ! !!!! !! ! !! ! ! ! ! ! !! ! ! ! ! ! !! ! ! !! ! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! !! ! ! ! ! ! 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