Combinatorial Design of Molecule using Activity-Linked Substructural Topological Information as Applied to...

Generating a large number of compounds using combinatorial methods increases the possibility of finding novel bioactive compounds. Although some combinatorial structure generation algorithms are available, any method for generating structures from activity-linked substructural topological information is not yet reported.

To develop a method using graph-theoretical techniques for generating structures of antitubercular compounds combinatorially from activity-linked substructural topological information, predict activity and prioritize and screen potential drug candidates.

Activity related vertices are identified from datasets composed of both active and inactive or, differently active compounds and structures are generated combinatorially using the topological distance distribution associated with those vertices. Biological activities are predicted using topological distance based vertex indices and a rule based method. Generated structures are prioritized using a newly defined Molecular Priority Score (MPS).

Studies considering a series of Acid Alkyl Ester (AAE) compounds and three known antitubercular drugs show that active compounds can be generated from substructural information of other active compounds for all these classes of compounds. Activity predictions show high level of success rate and a number of highly active AAE compounds produced high MPS score indicating that MPS score may help prioritize and screen potential drug molecules. A possible relation of this work with scaffold hopping and inverse Quantitative Structure-Activity Relationship (iQSAR) problem has also been discussed.

The proposed method seems to hold promise for discovering novel therapeutic candidates for combating Tuberculosis and may be useful for discovering novel drug molecules for the treatment of other diseases as well.