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DavidsonX – D001x – Medicinal Chemistry Chapter 11 – Lead Optimization Part 1 – Introduction Video Clip – Feedback Cycle Recall the picture of molecular space, specifically potential drug space. Most of the space is devoid of activity. Islands of hit-level activity are interspersed throughout the entirety of molecular space. Within hit spaces are possibly regions that contain leads, and the lead spaces may contain even smaller pockets of drug-quality molecules. Also remember that the lead discovery process starts with a search for hits, which are generally modified somewhat to afford promising leads. With a lead in hand, the lead optimization process can begin. Around the start of lead optimization, the lead is extensively analyzed. New versions of the lead with missing parts are synthesized in order to determine whether each part is critical to the target binding of the lead. In this fashion, the pharmacophore of the lead can be discovered. Knowing the pharmacophore provides two key pieces of information. First, the medicinal chemistry group knows where on the lead changes have the maximum impact on target binding. Second, the med chem group knows less sensitive parts of the lead. At these less sensitive areas modifications can be made to affect non-binding aspects, namely pharmacokinetics. The goal of lead optimization is to improve the properties of the lead to the extent that a marketable drug may be discovered. The lead optimization process is generally an iterative process. New compounds, called analogues, are made. The analogues are at least somewhat closely related structurally to the original lead. New analogues are tested for target binding as well as other properties, including cell permeability and liver metabolism. New analogues with less favorable properties are abandoned, and compounds with more favorable properties undergo further modification in an effort find a subsequent analogue with even better properties. The overall appearance of this process is a fractured, meandering walk through molecular space. In the scheme below, dots toward the left have less desirable properties. Dots on the right are more promising. The black dots represent synthesized compounds that were not pursued. The red dots and blue arrows show the progress of the lead as it starts from a hit and advances ultimately to a drug. A diagram of this sort for a real drug discovery program would have thousands of dots. inactive molecular space

hit space

lead space

drug space

final drug hit from screen improving drug properties

initial lead

MOOC Medicinal Chemistry