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Ensemble-based virtual screening: identification of a potential allosteric inhibitor of Bcr-Abl

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Abstract

Ensemble-based virtual screening using different conformations of a target protein is gaining popularity, as it can leverage information from target flexibility for effective lead identification. In this paper, molecular dynamics simulation followed by RMSD-based clustering was employed to generate and choose distinct conformations of Bcr-Abl. Three representative structures from the most-populated clusters along with the crystal structure conformation (PDBID: 3K5V) were used to perform docking-based virtual screening of 14,400 compounds (in the Maybridge database) in order to identify potential allosteric site binders. Seven compounds found as hits in at least three of the four virtual screenings had higher Glide docking scores than the co-crystallized allosteric inhibitor GNF-2. Detailed computational analyses of the seven hits identified SEW02675 (ΔG bind = −164.92 kJ/mol with the wild-type (wt) Bcr-Abl and −167.37 kJ/mol with the T334I Bcr-Abl mutant) as a better allosteric site binder with both the wt and the mutant Bcr-Abl protein than the reference allosteric inhibitor GNF-2 (ΔG bind = −103.12 with wt and −142.96 kJ/mol with T334I). Moreover, the presence of SEW02675 in the allosteric site enhanced the binding of imatinib (ΔG bind = −367.58 with wt and −294.56 kJ/mol with T334I) to the ATP sites of the wt and the mutant Bcr-Abl. However, when GNF-2 was present in the allosteric site, the binding of imatinib (ΔG bind = −351.76 with wt and −273.94 kJ/mol with T334I) to the ATP site was weaker. The in silico findings suggest that SEW02675 could be used in combination with imatinib to treat chronic myeloid leukemia, and that it could help to overcome resistance due to T334I Bcr-Abl mutation.

Virtual screening strategy to identify allosteric inhbitors of Bcr-Abl for the treatment of Chronic myeloid leukemia.

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Acknowledgements

A fellowship from Pondicherry University to VKS to pursue a Ph.D. and financial support from the University Grants Commission (F. no. 41-981/2012, SR), the Department of Biotechnology (BT/246/NE/TBP/2011/77), and the Science and Engineering Research Board (SR/FT/LS-64/2011), Govt. of India, to MSC are gratefully acknowledged.

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  1. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, 605014, India

    Vivek Kumar Singh & Mohane Selvaraj Coumar

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Correspondence to Mohane Selvaraj Coumar.

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Singh, V.K., Coumar, M.S. Ensemble-based virtual screening: identification of a potential allosteric inhibitor of Bcr-Abl. J Mol Model 23, 218 (2017). https://doi.org/10.1007/s00894-017-3384-y

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