Predictive models, based on classification algorithms, for compounds potentially active as mitochondrial ATP-sensitive potassium channel openers.
Heart mitochondrial ATP-sensitive potassium channel (mito-K(ATP) channels) are deeply implicated in the self-defense mechanism of ischemic preconditioning. Therefore, exogenous molecules activating these channels are considered as a promising pharmacological tool to reduce the myocardial injury deriving from ischemia/reperfusion events. In our laboratory, a series of 4-spiro-substituted benzopyran derivatives were earlier synthesized and some of them exhibited anti-ischemic properties. In this study, the above compounds are exploited in order to develop QSAR models, based on classification approaches, capable of discriminating between the ones acting as cardioprotective agents and those that are unable to elicit such a property. Molecules belonging to the whole dataset were subjected to CODESSA and E-Dragon calculations in order to compute a large number of molecular descriptors enabling the construction of classification models. Based on the two program packages used, two different experiments were carried out, with the aim of identify batteries of models to be exploited for designing new cardioprotective agents from libraries of new chemical entities. Both model batteries satisfy the rigorous criteria adopted for the validation, either when tested on the training and test set, according to the most straightforward protocol, and when tested on an additional prediction set. They were proven to ensure successful applications in the field of cardioprotective agent design.
Coi
Alessio
A
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Bianucci
Anna Maria
AM
Calderone
Vincenzo
V
Testai
Lara
L
Digiacomo
Maria
M
Rapposelli
Simona
S
Balsamo
Aldo
A
D000465:Algorithms; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology*; D054086:KATP Channels / Q000378:metabolism*; D008956:Models, Chemical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology
D001578:Benzopyrans; D002316:Cardiotonic Agents; D054086:KATP Channels; D013141:Spiro Compounds