Understanding the efficacy, potency, pharmacokinetics, and safety of compounds is important, but compounds almost always require improvement in their properties in order to become drugs. The process of improvement is called lead optimization and requires a thorough understanding of how a molecule’s structure affects its function, whether efficacy, PK, or toxicity. Unraveling a compound’s structure-function relationship enables lead optimization and hopefully results in the discovery of a compound that can be advanced into clinical trials.
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In this course about lead selection and lead optimization, students will learn methods for discovering and optimizing leads with the end goal of advancing a compound into the clinic. The three-week course starts with the processes for finding molecules with promising activity for initiation of a drug program. The second week covers the criteria used to select the best molecules as new leads for the optimization stage. In the final week, students will learn different methods for identifying structural changes that will optimize a lead’s efficacy and PK properties as well as reduce toxicity.
Students in the course should understand pharmacodynamics, drug activity, pharmacokinetics, and preclinical safety. Students should also be comfortable with algebraic expressions, including logarithmic and exponential functions. A fundamental understanding of the structure of organic molecules and their functional groups is also required. The course is designed in modules. Each module opens with a short video on a selected topic. The module continues with a short reading or exercise with an assessment activity. Each module will require approximately 1 hour to complete, and the course includes 15 modules. Two approaches to the course are recommended. One, a student might spend an hour per day on the course and complete all 15 modules in approximately three weeks. Two, a student with additional available time may be able to work through the entire course in just a single week or over an extended weekend.
Students signed up for the Audit Track have access to the instructional video materials. Students enrolled through the Verified Track have access to the instructional videos, the readings and activities, the assessments, as well as selected additional videos related to the primary instructional videos.
What you'll learn
- general approaches to finding compounds with activity on a drug target
- methods for confirming target engagement by an active compound
- techniques for communicating the pharmacophore of a series of active molecules
- criteria that help priorities biologically active compounds as potential leads
- types of information that are most often used to guide lead optimization decisions
- different functional groups that are often used to improve PK properties without affecting on-target activity in a molecule
Syllabus
week 1
actives, hits, leads, and clinical compounds
screening drug space for biological activity
types of screening libraries
hit confirmation and hit validation
drug-target binding
week 2
pharmacophore determination
lead selection
lead optimization
lead-like vs. drug-like
properties, metrics, and parameters
week 3
x-ray crystallography and cocrystals
structural changes for lead optimization
matched pair analysis and single point modifications
isosteres and bioisosteres
purity and in vivo toxicity
