basic concepts of profiling drug

Methods for Profiling Drug-like Properties: General Concepts : 

Methods for Profiling Drug-like Properties: General Concepts Edward H. Kerns and Li Di Presentation by Fei Xiang

Overview : 

Overview What should property profiling be? Property profiling should be rapid and use relevant assay conditions. What kind of assays can be used? Use a diverse set of assays that have high impact for the organization. Why assays should be carefully implemented? Property assays consume resources and influence projects. What should be evaluated? Evaluate the cost versus benefit of assays 11/12/2009 Design by Fei Xiang 2

Intruduction : 

Intruduction Assessment of compound properties has become an integral activity in drug discovery Assessment of compound properties provides data for the selection of leads the development of structure–property relationships(SPR) the judging of whether project advancement criteria have been met guide property optimization by structural modification 11/12/2009 3 Design by Fei Xiang

Property Data Should be Rapidly Available : 

Property Data Should be Rapidly Available 11/12/2009 Design by Fei Xiang 4

Why Faster is Better : 

Why Faster is Better 11/12/2009 Design by Fei Xiang 5

Use Relevant Assay Conditions : 

Use Relevant Assay Conditions What enviroment should assay conditions relevant to ? Conditions need to be relevant to the environment faced by the compound. What are the variables of property assays? Concentration pH matrix components in solution biological tissue extracts What is the requirement for these variables? Variables must be controlled and designed to be reflective of the barriers faced by the compound 11/12/2009 Design by Fei Xiang 6

Use appropritate assay for the particular stage : 

Use appropritate assay for the particular stage Earlier stages to select compounds Higer-throughput and Simpler methods In vitro enzyme receptor assays Later stages to optimize lead series Functional cell-based assays In vivo models 11/12/2009 Design by Fei Xiang 7 Fig. Graphical representation of drug-like chemical space.

Example of overkill : 

Example of overkill Mission: To select the most favorable from among the fatally flawed compounds in early stage Bad choice = Overkill methods : Use of Caco-2 for hits in early stage Good choice: Simpler methods provide sufficient information Structural rules on lipophilicity Polar surface area High-throughput parallel artificial membrane permeability assay (PAMPA) methods 11/12/2009 Design by Fei Xiang 8

Example of overinterpretation : 

Example of overinterpretation Use of data for solubility in an aqueous buffer at pH 7.4 as the primary solubility value in late discovery Why this is wrong choice? Solubility can be very different with the different pHs and concentrations of bile salts and lipids present throughout the length of the intestine 11/12/2009 Design by Fei Xiang 9

Evaluate the Cost-to-Benefit Ratio for Assays : 

Evaluate the Cost-to-Benefit Ratio for Assays Balances data needs and resources Resources should be used wisely Evaluate cost-to-benefit ratio of assays 11/12/2009 Design by Fei Xiang 10 $Cost ?Benifit

Choose an Ensemble of Key Properties to Evaluate : 

Choose an Ensemble of Key Properties to Evaluate 11/12/2009 Design by Fei Xiang 11 HT Assays All Compounds Custom Studies

Use Well-Developed Assays : 

Use Well-Developed Assays Data should be generated using well developed assays Examples: Data will be misleading if Compound is not soluble in the assay A high compound concentration saturates the enzyme Substrate turnover is too high A co-solvent inhibits the enzyme Conclusion Assay Conditions Can Greatly Affect The Results 11/12/2009 Design by Fei Xiang 12

How Scientists Analysis The Data of Assays : 

How Scientists Analysis The Data of Assays It is important that scientists generating the data Scientists generating the data validate the method against the known properties of well-characterized compounds using the data Scientists using the data know how data was generated discuss with the data generator Scientists discuss with the data generator how particular characteristics of the compounds in their series might affect the assay 11/12/2009 Design by Fei Xiang 13

Problems : 

Problems Is it useful to use data from a generic pH 7.4 solubility assay to predict solubility in the GI tract? No. The pH 7.4 conditions of the generic solubility assay are very different than the low pH conditions of the intestine. Is it useful to obtain Caco-2 A > B and B > A permeability data for 200 HTS hits for lead selection? No. The Caco-2 assay is too expensive at this level. Most of the HTS hits can be deprioritized using other, less expensive data or calculated properties. After less expensive triage, a smaller number of HTS hits can be run on Caco-2 for the final decisions on leads. Is PAMPA data at pH 7.4 sufficient for inclusion in the data package for clinical candidate nomination? No. Clinical candidate nomination should have a more rigorous data package that includes Caco-2 for permeability assessment. Is microsomal stability data sufficient for assessing the potential of hydrolysis? No. Hydrolysis can occur in the plasma and intestine and be catalyzed by numerous enzymes, which have different substrate specificity than microsomal hydrolysis enzymes. Is microsomal stability in multiple species necessary during lead optimization? Yes. Metabolic stability varies among species. Therefore, it is useful to have data for metabolic stability in rat (often used as the toxicology species), the project’s pharmacology/efficacy species (e.g., stability in transgenic mice can help with decisions on in vivo dosing and data interpretation if the pharmacology/efficacy species is transgenic), and human (assists predictions for clinical studies). 11/12/2009 Design by Fei Xiang 14

Summary : 

Summary Several aspects of the property profiling program are discussed Property Data Should be Rapidly Available Use Relevant Assay Conditions Evaluate the Cost-to-Benefit Ratio for Assays Choose an Ensemble of Key Properties to Evaluate Use Well-Developed Assays 11/12/2009 Design by Fei Xiang 15