Molecular Modeling Study on Diazine Indole Acetic Acid Derivatives for CRTH2 Inhibitory Activity

作者：Babu Sathya; Rupa Mottadi; Nagarajan Santhosh Kumar; Sohn Honglae^*; Madhavan Thirumurthy^*

来源：Combinatorial Chemistry & High Throughput Screening, 2016, 19(6): 444-460.

DOI：10.2174/1386207319666160502123759

• CRTH2
• Diazine indole acetic acid
• Topomer CoMFA
• HQSAR
• CoMFA
• CoMSIA

In the present work, molecular modeling studies have been reported on a series of diazine indole acetic acid derivatives to analyze the structure-activity relationship studies of CRTH2 using fragment (Topomer CoMFA and HQSAR) and field (CoMFA and CoMSIA) based QSAR methods. Twenty-six compounds were used as a training set to establish the model, and six compounds were used as a test set to validate the model. The generated models exhibited good statistical results such as correlation coefficient (r(2)) and the cross-validated correlation coefficient (q(2)). Topomer CoMFA analysis yielded the q(2) of 0.610 and r(2) of 0.981. HQSAR model generated using bond and connectivity as fragment distinction and 3-6 as fragment size has the q(2) value of 0.707 and conventional r(2) value of 0.892 with five components. CoMFA model was assessed by cross-validated q(2) value of 0.543 and r(2) value of 0.901 with steric and electrostatic fields. CoMSIA model generated using steric, hydrophobic and donor fields with q(2) value of 0.550 and r(2) value of 0.888 was found to be the optimal model among the various models generated. The contour maps were generated to analyze the important structural features that regulate their inhibitory potency. From the result of contour maps we have suggested the critical sites for chemical modification which will be useful in designing potent compounds with improved activity.

• 出版日期2016