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Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations

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Abstract

4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazines have been discovered as inhibitors of p38α. Experimental assays have proven that the configuration of α-Me-benzyl connected with amide at C6 is essential for the binding affinity. The S-configured inhibitor (11j) displays 80 times more potency than the R-configured one (11k). Here we investigated the mechanism how different configurations influence the binding affinity using molecular dynamics simulations, free energy calculations and free energy decomposition analysis. We found that the van der Waals interactions play the most important role in differentiating the activities between 11j and 11k with p38α. The difference of the van der Waals interactions is primarily determined by two residues, LEU108 and LEU167. Consequently stabilization of pyrrolo[2,1-f][1,2,4]triazine ring is important for the activities of inhibitors. Meanwhile we observed that the different configuration of the α-Me-benzyl group leads to the difference of binding between 11j and 11k. In conclusion, our work shows that it is feasible to analyze the chirality effect of inhibitors with different configurations by molecular dynamics simulations and free energy calculations, and provides useful information for drug design.

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Acknowledgments

The project was supported by the Natural Science Foundation of China (No. 20373089). We thank Prof. Xiaojie Xu in Department of Chemistry of Peking University for providing access to computer software such as AMBER.

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  1. College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, 100049, Beijing, People’s Republic of China

    Quan Chen, Wei Cui & Mingjuan Ji

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  1. Quan Chen
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Correspondence to Mingjuan Ji.

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Chen, Q., Cui, W. & Ji, M. Studies of chirality effect of 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine on p38α by molecular dynamics simulations and free energy calculations. J Comput Aided Mol Des 23, 737–745 (2009). https://doi.org/10.1007/s10822-009-9298-8

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