Analog based pharmacophore strategy to identify novel leukotriene a4 hydrolase (LTA4H) inhibitors

Kranthi Raj K.¹, Pathak L.P.², Muttineni Ravikumar³, Ramachandrana D.^4
1Acharya Nagarjuna University, P.G center, Nuzvid, 521201, Andhra Pradesh, India
²National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 5000 37, Andhra Pradesh, India
³Bioinformatics Division, Environmental Microbiology Lab, Department of Botany, Osmania University, Hyderabad 500007, Andhra Pradesh, India
⁴

Received : -     Accepted : -     Published : 21-12-2010
Volume : 2     Issue : 2       Pages : 20 - 50
Int J Drug Discov 2.2 (2010):20-50
DOI : http://dx.doi.org/10.9735/0975-4423.2.2.20-50

Keywords : Leukotriene A4 hydrolase (LTA4H), Pharmacophore
Conflict of Interest : None declared

Leukotriene A4 hydrolase (LTA4H) is a hydrolase with a bifunctional zinc enzyme, which plays a role in inflammation. LTA4H may also play an important role in carcinogenesis, especially chronic inflammation-associated carcinogenesis. In this study, chemical feature based pharmacophore models based on 22 currently available LTA4H inhibitors have been developed with the aid of HipHop and HypoRefine modules within Catalyst program package. 3D pharmacophore model developed was, characterized by distinct chemical features such as Hydrogen-bond acceptor (HA), Hydrogen-bond donor (HD), Hydrophobic aliphatic (HPAli), Hydrophobic aromatic (HPAr) that are found to be responsible for the activity of the LTA4H inhibitors. The correlation coefficient, root mean square deviation and cost difference were 0.92, 1.0867 and 53.62 respectively, suggesting that a highly predictive pharmacophore model was successfully obtained. The results of our study provide a valuable tool in designing new leads with desired biological activity for virtual screening.

[1] Chen X., Wang S., Wu N., Yang C.S. (2004) Current Cancer Drug Targets, 4 (3), 267-283  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[2] Bigby T.D., D. M. Lee., N. Meslier., D. C. Gruenert. (1989) Biochemical and Biophysical Research Communications, 164 (1), 1-7  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[3] Zheng Sun., Sood,S., Ning L., Ramji D., Yang P., Newman R.A., Yang C. S. and Chen X. (2006) Carcinogenesis, 27 (9), 1902-1908  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[4] Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N.,Weissig H., Shindyalov I. N., Bourne P. E. (2000) Nucleic Acids Res, 28(1), 235-242.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[5] Cerius 2, molecular modeling program package, Accelrys: San Diego, CA.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[6] Wu G., Robertson D.H., Brooks C.L. Vieth M. (2003) J Computational chemistry, 24(13), 1549–1562  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[7] Catalyst v4.10. Molecular Simulations. San Diego, CA.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[8] Grice C.A., Tays K.L., Savall B.M., Wei J., Butler C.R., Axe F.U., Bembenek S.D., Fourie A.M., Dunford P.J., Lundeen K., Coles F., Xue X., Riley J.P., Williams K.N., Karlsson L., Edwards J.P. (2008) Journal of Medicinal Chemistry, 51, 4150-4169  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[9] Kirkland T. A., Adler M., Bauman J.G., Chen M., Haeggström J.Z., King B., Kochanny M. J., Liang A. M., Mendoza L., Phillips G.B., Thunnissen G. B., Trinh L., Whitlow M., Ye B., Ye H., Parkinson J., Guilford W. J. (2008) Bioorganic & Medicinal Chemistry, 16(9), 4963-4983  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[10] Bin Ye, Bauman J., Chen M., Davey D., Khim S.K., King B., Kirkland T., Kochanny M., Liang A., Lentz D., May K., Mendoza L., Phillips G., Selchau V., Schlyer S., Tseng J.L., Wei R.G., Ye H., Parkinson J., Guilford W.J. (2008) Bioorganic & Medicinal Chemistry Letters 18(14), 3891-3894  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[11] Khim S.K., Bauman J., Evans J., Freeman B., King B., Kirkland T., Kochanny M., Lentz D., Liang A., Mendoza L., Phillips G., Tseng J.L., Wei R.G., Ye H., Yu L., Parkinson J., Guilford W.J. (2008) Bioorganic & Medicinal Chemistry Letters, 18(14), 3895-3898  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[12] Enomoto H., Morikawa Y., Miyake Y., Tsuji F., Mizuchi M., Suhara H., Fujimura K.I., Horiuchi, M., Ban M. (2008) Bioorganic & Medicinal Chemistry Letters 18 (16), 4529-4532.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[13] Enomoto H., Morikawa Y., Miyake Y., Tsuji F., Mizuchi M., Suhara H., Fujimura K.I., Horiuchi, M., Ban M. (2009), Bioorganic & Medicinal Chemistry Letters, 19 (2), 442-446  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[14] Smellie A., Teig S.L., Towbin P.(1995) Journal of Computational Chemistry, 16(2), 171–187.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus