Question

If you cut parts off of the lead compound and it keeps losing potency, what can you conclude? If that happens, what do you try next?

And, You cut a piece off of the lead, and the potency drops. When would it be beneficial to continue anyway with this truncated lead?

Answer 1

Lead compounds are the compounds having desired pharmacological activity. These compounds have suboptimal structures and requires modification to enable the the compound to fit better with the receptor.

The part of the lead compound involved in binding with specific receptor using intermolecular interactions between the functional groups is called the pharmacophore. The other regions of lead compound which are not involved in drug-receptor binding is called the auxophore or molecular baggage. The auxophore orient the functional groups of pharmacophore in a defined 3D pattern and maintain the structural integrity of the pharmacophore.

The drug discovery process starts from identifying the molecular target and proceed to lead compound identification. Lead compounds are then modified and optimized to enable the compond to possess the desired pharmacokinetic and pharmacodynamic properties.

By cutting pieces off the lead compound we can gain new insights into possible bioactive structures.

If cutting a piece off lead compound leads to :

• A decrease in potency of a lead compound suggest that it may have been pharmacophoric.
• An increase in potency means that it may have been auxophoric and interfere with proper binding.
• No change in potency means that it may have been auxophoric but not interfering with binding.

If a cut in lead compound produces a compound with lower potency, then the excision is removing part of the pharmacophore or the cut causes a confirmational change that results in a structure different from the bioactive conformation.

The conformational change is particularly relevant to rigid structures.

Functional groups can be added to the lead structure to increase the pharmacophore and thereby increase the potency of the drug.

Benefits of Truncated Leads:

• Truncated leads can be used to synthesize new leads and analogue componds.
• Truncated leads are used in retrospective evaluation of binding efficiency.