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Ask REGgie: Identifying chiral drug candidates

Q:  In a set of substances that share specific structural features, how can I identify which compounds both meet the Lipinski criteria* and have specific stereochemistry?

A:  After you have conducted a structure search in the CAS REGISTRY^SM database:

1. Limit the answer set to substances that meet the Lipinski criteria.
2. Restrict the answers to substances with specific chirality.

Applying Lipinski criteria

The Lipinski criteria for substances that are likely to have good oral bioavailability are:

• 5 or fewer hydrogen bond donors (/HD)
• 10 or fewer hydrogen bond acceptors (/HAC)
• Calculated logP (/LOGP) less than or equal to 5 
• Molecular weight (/MW) less than or equal to 500

In REGISTRY, you can limit your answer set in a single step to substances with these properties by using LIPINSKI/CALC.

Identifying chiral substances

Substances with known relative or absolute stereochemistry have STEREOSEARCH posted in the File Segment (/FS) field.

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Identify chiral drug candidates within a set of substances that share specific structural characteristics.

=> FIL REGISTRY  
Upload the structure query and perform a SAMPLE search.
=>  
Uploading C:\CASNC\STN Express\Queries\xyz3.str
L1      STRUCTURE UPLOADED
 
=> S L1
L2           25 SEA SSS SAM L1
 
A FULL search yields 533 substances.
 
=> S L1 FUL
L3          533 SEA SSS FUL L1
 
Refine answers by applying Lipinski criteria.**
 
=> S L3 AND LIPINSKI/CALC
      21318410 0-5/HD
      20457899 0-10/HAC
      17415509 LOGP <= 5
      17812663 0-500/MW
      14400208 LIPINSKI/CALC
                 (0-5/HD AND 0-10/HAC AND LOGP <= 5 AND
                  0-500/MW)
L4         320 L3 AND LIPINSKI/CALC
 
Limit to answers with specific chirality.
 
=> S L4 AND STEREOSEARCH/FS
       6952051 STEREOSEARCH/FS
L5          33 L5 AND STEREOSEARCH/FS
 
Display an answer.
 
=> D STR 
   
L5   ANSWER 1 OF 33  REGISTRY  COPYRIGHT 2007 ACS on STN
 
Relative stereochemistry. 
"Relative stereochemistry" indicates that the absolute configuration of the chiral centers is unknown. When it is known, the message reads "Absolute stereochemistry."
  
 
 

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Additional Resources

For additional information, enter HELP LIPINSKI at an arrow prompt (=>) in REGISTRY.

See also:

• STN Database Summary Sheet for REGISTRY
• STN User Documentation: Searching for Structures
• STN User Documentation: Searching for Property Data

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* Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.  Advanced Drug Delivery Reviews 1997, 23, 3-25.

** Any REGISTRY answer set may be refined by using this technique.