Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Discovery of potential inhibitors of BMX non-receptor tyrosine kinase through e-pharmacophore based virtual screening
Bone marrow kinase in the X chromosome (BMX), a Tec family kinase, play important role in monocyte/macrophage function and trafficking. BMX is expressed in bone marrow, granulo/monocytic cells and arterial endothelium. The stimulated production of IL-6, an important mediator of autoimmunity, has been shown to be dependent on BMX in human fibroblast-like synoviocytes by the use of siRNA knockdown (Semaan et al., 2008). IL-6 over expression is known to play critical role in progression of psoriasis (Saggini et al., 2014). BMX has been also shown to be overexpressed in human prostate cancer (Dai et al., 2006). This signifies discovery of potential BMX inhibitors would represent promising therapies for autoimmune disorders and decipher potential anti-cancer applications. Herein, two crystal structure of BMX in complex with inhibitors (3SXR and 3SXS) available at Protein databank were retrieved. The structures were refined using protein preparation wizard Maestro v9.8. The inhibitors were re-docked using Glide v6.3 to generate energy based pharmacophore based on interaction of known inhibitors to the ligand binding pocket (Fig. 1). e-pharmacophore based screening was performed from an in-house ligand database set up from more than one million entries of Ligand.Info database. A dataset of 1678 ligands matched to two pharmacophores with fitness score >1.2 were selected for three stage docking with BMX inhibitor binding pocket using virtual screening workflow (Pradhan et al., 2014). The ligands were screened based on extra precision Glide scores (XP Gscore). The top ranked ligands were re-scored using Prime/MM-GBSA free energy calculations (ΔG). The binding affinity and binding orientations of five ligands compared favorably with dasatinib and PP2,
Fig. 1: e-pharmacophore models A) BMX complex with dasatinib (3SXR) B) BMX complex with PP2 (3SXS)
hence, were proposed as potential BMX inhibitors (Fig. 2). The pharmacological properties of five leads were within the limits 95% of drug molecules. Therefore, design of therapeutic molecules based on the proposed e-pharmacophores and five potential BMX inhibitors through in vitro and in vivo analysis would be intriguing towards developing therapeutics for autoimmune disorders.
Fig. 2: Five proposed BMX inhibitors, Dasatinib and PP2.
Acknowledgement: We are highly thankful to ICMR for supporting Biomedical Informatics centre at National Institute of Pathology, New Delhi vide grant No: NIP/ICMR (Biomedical Informatics Centre;s of ICMR)/AKJ/2014-15/1429. Authors also acknowledge BIF at SVIMS University, Tirupati.
Dai, O. Kim, Y. Xie, Z. Guo, K. Xu, B. Wang, X. Kong, J. Melamed, H. Chen, C. J. Bieberich, A.D. Borowsky, H.J. Kung, G. Wei, M.C. Ostrowski, A. Brodie, Y. Qiu (2006) Tyrosine kinase Etk/Bmx is up-regulated in human prostate cancer and its overexpression induces prostate intraepithelial neoplasia in mouse. Cancer Res. 66, 8058Ã�Â¢-8064.
Pradhan, I.V. Priyadarshini, M. Munikumar, S. Swargam, A. Umamaheswari, B. Aparna (2014) Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC of Leptospira spp.: Homology modeling, docking and molecular dynamics study. J. Biomol. Struct. Dyn. 32,171-185.
N. Semaan, G. Alsaleh, J.E. Gottenberg, D. Wachsmann, J. Sibilia (2008) Etk/Bmx, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J. Immunol. 180, 3485-3491.
Dibyabhaba Pradhan 1*
1Biomedical Informatics Centre of ICMR