Abstract
A novel approach termed comparative residue-interaction analysis (CoRIA), emphasizing the trends and principles of QSAR in a ligand–receptor environment has been developed to analyze and predict the binding affinity of enzyme inhibitors. To test this new approach, a training set of 36 COX-2 inhibitors belonging to nine families was selected. The putative binding (bioactive) conformations of inhibitors in the COX-2 active site were searched using the program DOCK. The docked configurations were further refined by a combination of Monte Carlo and simulated annealing methods with the Affinity program. The non-bonded interaction energies of the inhibitors with the individual amino acid residues in the active site were then computed. These interaction energies, plus specific terms describing the thermodynamics of ligand–enzyme binding, were correlated to the biological activity with G/PLS. The various QSAR models obtained were validated internally by cross validation and boot strapping, and externally using a test set of 13 molecules. The QSAR models developed on the CoRIA formalism were robust with good r 2, q 2 and r 2pred values. The major highlights of the method are: adaptation of the QSAR formalism in a receptor setting to answer both the type (qualitative) and the extent (quantitative) of ligand–receptor binding, and use of descriptors that account for the complete thermodynamics of the ligand–receptor binding. The CoRIA approach can be used to identify crucial interactions of inhibitors with the enzyme at the residue level, which can be gainfully exploited in optimizing the inhibitory activity of ligands. Furthermore, it can be used with advantage to guide point mutation studies. As regards the COX-2 dataset, the CoRIA approach shows that improving Coulombic interaction with Pro528 and reducing van der Waals interaction with Tyr385 will improve the binding affinity of inhibitors.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Hansch C, Maloney PP, Fujita T, Muir RM (1962) Nature 194:178
Hansch C, Muir RM, Fujita T, Maloney PP, Geiger CF, Streich M (1963) J Am Chem Soc 85:2817
Hansch C, Fujita T (1964) J Am Chem Soc 86:5175
Cramer RD III, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959
Tokarski JS, Hopfinger AJ (1994) J Med Chem 37:3639
Klebe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130
Havel TF, Kuntz ID, Crippen GM (1983) Bull Math Biol 45:665
Doweyko AM (1988) J Med Chem 31:1396
Walters DE, Hinds RM (1994) J Med Chem 37:2527
Jain AN, Koile K, Chapman D (1994) J Med Chem 37:2315
Müller K (ed) (1995) Perspectives in drug discovery and design, vol 3. ESCOM Science Publishers, BV, Leiden, pp 1–20
Nelson LM, Malhotra D, Hopfinger AJ (1981) Comput Chem 5:19
Ortiz AR, Pisabarro MT, Gago F, Wade RC (1995) J Med Chem 38:2681
Gohlke H, Klebe G (2002) J Med Chem 45:4153
Vedani A, Briem H, Dobler M, Dollinger K, McMasters DR (2000) J Med Chem 43:4416
Vedani A, Dobler M (2002) J Med Chem 45:2139
Vedani A, Dobler M, Lill L (2005) J Med Chem 48:3700
Tokarski JS, Hopfinger AJ (1997) J Chem Info Comput Sci 37:792
Charifson PS (ed) (1997) Practical application of computer-aided drug design, Marcel Dekker Inc., pp 355–410
Delphi 2.5, User Guide. Accelrys Inc., San Diego, CA, USA
Scott WR, Schiffer CA (2000) Structure Fold Des 8:1259
Charifson PS (ed) (1997) Practical application of computer-aided drug design. Marcel Dekker Inc., pp 495–538
Knetgel RMA, Grootenhuis PDJ (1998) Perspect Drug Discov Des 9–11:99
Williams DH, Cox JPL, Doig AJ, Garner M, Gerhard U, Kaye PT, Lal AR, Nicholls IA, Salter J, Mitchell RC (1991) J Am Chem Soc 113:7020
InsightII, version 2000.3 L. Accelrys Inc., San Diego, CA, USA
Dauber-Osguthorpe P, Roberts VA, Osguthorpe DJ, Wolff J, Genest M, Hagler AT (1988) Proteins 4:31
Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE (1982) J Mol Biol 161:269
Affinity v. 98 Molecular Modeling Program Package. Accelrys Inc. San Diego, CA, 1998
Cerius2 version 4.8. Accelrys Inc., San Diego CA, 1999
Khanna IK, Weier RM, Yu Y, Collins PW, Miyashiro JM, Koboldt CM, Veenhuizen AW, Currie JL, Seibert K, Isakson PC (1997) J Med Chem 40:1619
Khanna IK, Weier RM, Yu Y, Xu XD, Koszyk FJ, Collins PW, Koboldt CM, Veenhuizen AW, Perkins WE, Casler JJ, Masferrer JL, Zhang YY, Gregory SA, Seibert K, Isakson PC (1997) J Med Chem 40:1634
Khanna IK, Yu Y, Huff RM, Weier RM, Xu X, Koszyk FJ, Collins PW, Cogburn JN, Isakson PC, Koboldt CM, Masferrer JL, Perkins WE, Seibert K, Veenhuizen AW, Yuan J, Yang DC, Zhang YY (2000) J Med Chem 43:3168
Reitz DB, Li JJ, Norton MB, Reinhart EJ, Collins JT, Anderson GD, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Isakson PC (1994) J Med Chem 38:3878
Li JJ, Anderson GD, Burton EG, Cogburn JN, Collins JT, Garland DJ, Gregory SA, Huang HC, Isakson PC, Koboldt CM, Logusch EW, Norton MB, Perkins WE, Reinhart EJ, Seibert K, Veenhuizen AW, Zhang Y, Reitz DB (1995) J Med Chem 38:4570
Li JJ, Norton MB, Reinhart EJ, Anderson GD, Gregory SA, Isakson PC, Koboldt CM, Masferrer JL, Perkins WE, Seibert K, Zhang Y, Zweifel BS, Reitz DB (1996) J Med Chem 39:1846
Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC (1997) J Med Chem 40:1347
Huang HC, Li JJ, Garland DJ, Chamberlain TS, Reinhart EJ, Manning RE, Seibert K, Koboldt CM, Gregory SA, Anderson GD, Veenhuizen AW, Zhang Y, Perkins WE, Burton EG, Cogburn JN, Isakson PC, Reitz DB (1996) J Med Chem 39:253
Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K (2000) J Med Chem 43:775
Lee LF (1996) Pat. No. WO 9624585, US
Song Y, Connor DT, Doubleday R, Sorenson RJ, Sercel AD, Unangst PC, Roth BD, Gilbertsen RB, Chan K, Schrier DJ, Guglietta A, Bornemeier DA, Dyer RD (1999) J Med Chem 42:1151
Song Y, Connor DT, Sercel AD, Sorenson RJ, Doubleday R, Unangst PC, Roth BD, Gilbertsen RB, Chan K, Schrier DJ, Guglietta A, Bornemeier DA, Dyer RD (1999) J Med Chem 42:1161
Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Nature 384:644
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235
MS, QCPE. Creative Arts Bldg. 181, Indiana University, Bloomington, IN 47405
Ding HQ, Karasawa N, Goddard WA III (1992) J Chem Phys 97:4309
Nicholls A, Honig B (1991) J Comput Chem 12:435
Maple JR, Hwang M-J, Stockfisch TP, Dinur U, Waldman M, Ewig CS, Hagler AT (1994) J Comput Chem 15:162
Dixit SB, Bhasin R, Rajasekaran E, Jayaram B (1997) J Chem Soc Faraday Trans 93:1105
Waller CL, Marshall GR (1993) J Med Chem 36:2390
Kodithala K, Hopfinger AJ, Thompson ED, Robinson MK (2002) Toxicol Sci 66:336
Stanton DT, Jurs PC (1990) Anal Chem 62:2323
Ghose A, Crippen G (1986) J Comput Chem 7:565
Rogers D, Hopfinger AJ (1994) J Chem Inf Comput Sci 34:854
Kubinyi H. (ed) (1993) 3D QSAR in drug design: theory, methods and applications, ESCOM, Leiden, pp 523–550
Cerius2 4.8, User’s Manual. Accelrys Inc., San Diego, CA, USA
Vieth M, Cummins DJ (2000) J Med Chem 43:3020
Ryn JV, Trummlitz G, Pairet M (2000) Curr Med Chem 7:1145
Shimokawa T, Kulmacz RJ, DeWitt DL, Smith WL (1990) J Biol Chem 265:20073
Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, Marnett LJ (2000) Proc Natl Acad Sci USA 97:925
So OY, Scarafia E, Mak AY, Callan OH, Swinney DC (1998) J Biol Chem 273:5801
Greig GM, Francis DA, Falgueyret JP, Ouellet M, Percival MD, Roy P, Bayly C, Mancini JA, O’Neil GP (1997) Mol Pharmacol 52:829
Desiraju GR, Gopalakrishnan B, Jetti RKR, Raveendra D, Sarma JARP, Subramanya HS (2000) Molecules 7:945
Chavatte P, Yous S, Lesieur D (2001) J Med Chem 44:3223
Liu H, Huang X, Shen J, Luo X, Li M, Xiong H, Chen G, Shen J, Yang Y, Jiang H, Chen K (2002) J Med Chem 45:4816
Datar PA, Coutinho EC (2004) J Mol Graph Model 23:239
Kim H-J, Chae CH, Yi KY, Park K-L, Yoo S (2004) Bioorg Med Chem 12:1629
Acknowledgements
This work was made possible by a grant [01(1986)/05/EMR-II] from the Council of Scientific and Industrial Research (CSIR), New Delhi to E. C. Coutinho. S. A. Khedkar and A. K. Malde thank CSIR for financial support. We thank Dr. Krishna Iyer for useful suggestions during the course of this work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Datar, P.A., Khedkar, S.A., Malde, A.K. et al. Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands. J Comput Aided Mol Des 20, 343–360 (2006). https://doi.org/10.1007/s10822-006-9051-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10822-006-9051-5