Abstract
Docking and three dimensional quantitative-structure activity relationship (3D-QSAR) studies were performed on acetohydroxy acid synthase (AHAS) inhibitor sulfonylurea analogues with potential herbicidal activity. The 3D-QSAR studies were carried out using shape, spatial and electronic descriptors along with a few structural parameters. Genetic function approximation (GFA) was used as the chemometric tool for this analysis. The whole data set (n = 45) was divided into a training set (75% of the data set) and a test set (remaining 25%) on the basis of the K-means clustering technique on a standardised topological, physicochemical and structural descriptor matrix. Models developed from the training set were used to predict the activity of the test set compounds. All models were validated internally, externally and using the Y-randomisation technique. Docking studies suggested that the molecules bind within a pocket of the enzyme formed by some important amino acid residues (Met351, Asp375, Arg377, Gly509, Met570 and Val571). In QSAR studies, molecular shape analysis showed that bulky substitution at the R1 position may enhance AHAS inhibitory activity. Charged surface area descriptors suggested that negative charge distributed over a large surface area may enhance this activity. The hydrogen bond acceptor parameter supported the charged surface area descriptors and suggested that, for better activity, the number of electronegative atoms present in the molecule should be high. The spatial descriptors show that, for better activity, the molecules should possess a bulky substituent and a small substitution at the R2 and R3 positions, respectively.
Similar content being viewed by others
References
Estrada E, Uriarte E, Montero A, Teijeira M, Santana L, De Clercq E (2000) J Med Chem 43:1975–1985
González MP, Dias LC, Helguera AM, Rodríguez YM, De Oliveira LG, Gómez LT, Díaz HG (2004) Bioorg Med Chem 12:4467–4475
González MP, González Díaz H, Molina RR, Cabrera MA, Ramos de Armas R (2003) J Chem Inf Comput Sci 43:1192–1199
González MP, Terán C, Teijeira M, Helguera AM (2006) Curr Med Chem 13:2253–2266
Xiao Z, Xiao YD, Feng J, Golbraikh A, Tropsha A, Lee KH (2002) J Med Chem 45:2294–2309
González-Díaz H, Torres-Gómez LA, Guevara Y, Almeida MS, Molina R, Castañedo N, Santana L, Uriarte E (2005) J Mol Model 11:116–123
Yang GF, Huang X (2006) Curr Pharm Des 12:4601–4611
Peng H, Wang T, Xie P, Chen T, He H, Wan J (2007) J Agric Food Chem 55:1871–1880
Zhang L, Wan J, Yang G (2004) Bioorg Med Chem 12:6183–6191
Wang JG, Li ZM, Ma N, Wang BL, Jiang L, Pang SS, Lee YT, Guddat LW, Duggleby RG (2005) J Comput Aided Mol Des 19:801–820
Zhu YQ, Liu P, Si XK, Zou XM, Liu B, Song HB, Yang HZ (2006) J Agric Food Chem 54:7200–7205
Xi Z, Yu Z, Niu C, Ban S, Yang G (2006) J Comput Chem 27:1571–1576
Schloss JV (1990) Pest Manag Sci 29:283–292
McCourt JA, Pang SS, King-Scott J, Guddat LW, Duggleby RG (2006) Proc Natl Acad Sci USA 103:569–573
Kirkpatrick P (2004) Nat Rev Drug Discov 3:299
Discovery Studio 2.0 is a product of Accelrys Inc, San Diego, CA
Cerius2 Version 4.10 is a product of Accelrys Inc, San Diego, CA
Eriksson L, Jaworska J, Worth AP, Cronin MTD, McDowell RM (2003) Environ Health Perspect 111:1361–1375
Guha R, Jurs PC (2005) J Chem Inf Model 45:65–73
Leonard JT, Roy K (2006) QSAR Comb Sci 25:235–251
Roy K (2007) Expert Opin Drug Discov 2:1567–1577
Everitt B, Landau S, Leese M (2001) Cluster analysis. Arnold, London
Dougherty ER, Barrera J, Brun M, Kim S, Cesar RM, Chen Y, Bittner M, Trent JM (2002) J Comput Biol 9:105–126
Hopfinger AJ, Tokarsi JS (1997) In: Charifson PS (ed) Practical applications of computer-aided drug design. Dekker, New York
Rogers D, Hopfinger AJ (1994) J Chem Inf Comput Sci 34:854–866
Roy PP, Leonard JT, Roy K (2008) Chemom Intell Lab Sys 90:31–42
Kubinyi H, Hamprecht FA, Mietzner T (1998) J Med Chem 41:2553–2564
Marshall GR (1994) In: Kubinyi H (ed) 3D QSAR in drug design—theory, methods and applications. ESCOM, Leiden
Deswal S, Roy N (2006) Eur J Med Chem 41:1339–1346
MINITAB is a statistical software of Minitab Inc, State College, PA
SPSS is a statistical software of SPSS Inc., Chicago, IL
Unger SH, Hansch C (1973) J Med Chem 16:745–749
Golbraikh A, Tropsha A (2002) J Mol Graph Model 20:269–276
Roy PP, Roy K (2008) QSAR Comb Sci 27:302–313
Roy PP, Roy K (2008) Chem Biol Drug Des 72:370–382
Roy K, Paul S (2009) QSAR Comb Sci 28:406–425
Acknowledgement
Financial assistance from the Ministry of Human Resource Development, Government of India, New Delhi, in the form of a scholarship to S.P. is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Roy, K., Paul, S. Docking and 3D-QSAR studies of acetohydroxy acid synthase inhibitor sulfonylurea derivatives. J Mol Model 16, 951–964 (2010). https://doi.org/10.1007/s00894-009-0596-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00894-009-0596-9