Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Structure guided novel lead molecules against ERK proteins: Application of multiple docking and molecular dynamics studies

Human extracellular regulated kinase (ERK1 and ERK2) proteins are serine/threonine protein-kinases; these two proteins having 88% sequence similarity and also the ATP binding site residues. ERKs are playing pivotal role in Ras-Raf-MEK-ERK in the pathway which participate in the cellular process includes cell adhesion, cell cycle progression, cell migration, cell survival, cell differentiation, cell metabolism, cell proliferation, and cell transcription. Over-expression or mutations of this cascade proteins are increased in about one-third of all human cancers includes lung, ovary, kidney, colon and pancreas. In order to develop therapeutics for cancer, ERK protein kinases can be potentially a good target (Aronov et al., 2007; Larif et al., 2014). In the present study, goal is to discover novel lead molecules for ERK based on structure guided process. 20 co-crystal structures were prepared and docked with the referred crystal ligand and 20 energy based pharmacophores were obtained using the PHASE v4.1. Four common pharmacophores were developed (Fig.1) and screened towards the shape based screening using 3D-Database (One million compounds) and 1750 compounds were obtained. These were applied to sequential molecular docking (HTVS, SP and XP) with the 4QTA in Glide v6.5. The best docked ten leads were further applied for QPLD, IFD and MM-GBSA analysis (Du et al., 2011). Lead 1 and 2 (Fig.2) exhibited better XPGscore (-9.59 k.cal/mol; -9.06 k.cal/mol) and binding interactions than the 20 crystal ligands. The best two leads were proposed and applied to the molecular dynamics simulations. Docking, molecular dynamics simulations and ADME property predictions showed higher potency of the leads which would be exciting towards the development of potent inhibitor towards the ERK.


I highly acknowledge to ICMR, Govt. of India, for sanctioning the SRF (No.BIC/11(09)/2013). The authors are highly thankful to DBT, ministry of science and technology, Govt. of India for providing all facilities to carry out the work in SVIMS Bioinformatics centre (BT/BI/04/055/2001, 22nd Sep 2006).

    A.M. Aronov, C. Baker, G.W. Bemis, J. Cao, G. Chen, P.J. Ford, U.A. Germann, J. Green, M.R. Hale, M. Jacobs, J.W. Janetka, F. Maltais, G. Martinez-Botella, M.N.Namchuk, J.Straub, Q. Tang, X. Xie. (2007). Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors. J Med Chem 22, 1280-1287.

    J. Du, H. Sun, L. Xi, J. Li, Y. Yang, H. Liu, X. Yao. (2011). Molecular modeling study of checkpoint kinase 1 inhibitors by multiple docking strategies and prime/MM-GBSA calculation. J Comput Chem 32, 2800-2809.

    S. Larif, C. Ben Salem, H. Hmouda, K. Bouraoui. (2014). In silico screening and study of novel ERK2 inhibitors using 3D QSAR, docking and molecular dynamics. J Mol Graph Model 53, 1-12.

Sandeep Swargam *
Dibyabhaba Pradhan
Natarajan Pradeep
Kanipakam Hema
Vagolu Siva Krishna
Amineni Umamaheswari**

Bioinformatics Centre
Department of Bioinformatics
Sri Venkateswara Institute of Medical Science University
Andhra Pradesh 517507, India
*Presenting Author
**Corresponding Author

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