Abstract
Two different scoring functions, Hirshfeld fingerprint-based scoring (HFBS) and molecular operating environment (MOE), and the kernel energy method (KEM) along with counterpoise (CP)-corrected approach were used to estimate the binding energies of protein–ligand complexes and tested against a series of inhibitors of human aldose reductase enzyme. The new scoring function, HFBS, is based on Hirshfeld fingerprints, which are 2D histogram plots of the distances from the molecular Hirshfeld surface to the nearest atomic nuclei inside versus outside the surface and are highly sensitive to the immediate environment of the molecule. The Hirshfeld surface plotted over the ligand molecule helped to visualize the contacts with the active site residues and solvents, which were then taken into account for interaction energy calculations. Application of KEM-assisted CP-corrected approach facilitated an efficient way of calculating interaction energies in protein complex systems. Interaction energies calculated using MP2/6-31G(d) level of theory allowed us to rank the ligands by potency. We find that both the KEM-assisted CP-corrected interaction energies and the scoring functions used here predict comparable rankings for the strength of binding of the series of ligands as docked to the active site of the protein, which are also in good agreement with the experimental binding affinities in this case.
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References
Gohlke H, Hendlich M, Klebe G (2000) J Mol Biol 295(2):337–356
Gohlke H, Hendlich M, Klebe G (2000) Perspect Drug Disc Des 20(1):115–144
Huang SY, Zou X (2006) J Comput Chem 27(15):1876–1882
Huang L, Massa L, Karle J (2005) Int J Quantum Chem 103:808–817
Řezáč J, Dennis R, Salahub DR (2010) J Chem Theory Comput 6:91–99 and the references therein
Huang L, Massa L, Karle J (2005) Biochemistry 44:16747–16752
Huang L, Massa L, Karle J (2006) Proc Natl Acad Sci 103:1233–1237
Huang L, Massa L, Karle J (2005) Proc Natl Acad Sci 102:12690–12693
Huang L, Massa L (2012) Future Med Chem 4:1479–1494
Frisch MJ, Head-Gordon M, Pople JA (1990) Chem Phys Lett 166:275–280
Head-Gordon M, Pople JA, Frisch MJ (1988) Chem Phys Lett 153:503–506
Boys SF, Bernardi F (1970) Mol Phys 19:553
Simon S, Duran M, Dannenberg JJ (1996) J Chem Phys 105:11024–11031
Halkier A, Klopper W, Helgaker T, Torgensen P, Taylor PR (1999) J Chem Phys 111:9157–9168
van Duijneveldt FB, van Duijneveldt- van de Rijdt JGCM, van Lenthe JH (1994) Chem Rev 7:1873–1885
Ferrari AM, Degliesposti G, Sgobba M, Rastelli G (2007) Bioorg Med Chem 15:7865–7877
Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D (2004) Proteins Struct Funct Bioinf 55(4):792–804
Labute P (2011) Molecular operating environment. Chemical Computing Group, Inc., Montreal, Quebec, Canada
Bader RFW (1990) Atoms in molecules: a quantum theory. Oxford, Oxford
Hirshfeld FL (1977) Theor Chim Acta 44:129
Ayers PW (2006) Theor Chem Accounts 115:370–378
Bultinck P, Ayers PW, Fias S, Tiels K, Van Alsenoy C (2007) Chem Phys Lett 444:205–208
Bultinck P, Cooper DL, Van Neck D (2009) Phys Chem Chem Phys 11:3424–3429
Spackman MA, Jayatilaka D (2009) CrystEngComm 11(1):19–32
Munshi P, Skelton BW, JJ MK, Spackman MA (2008) CrystEngComm 10:197–206
Huang L, Massa L, Karle J (2007) Proc Natl Acad Sci 104:4261–4266
Dixon SL, Jurs PC (1993) ChemAxon Ltd J Comput Chem 14:1460
Halgren TA (1996) J Comput Chem 17:490–519
The PyMol molecular graphics system, version 1.8. LLC, Schrödinger
Corbeil CR, Williams CI, Labute P (2012) J Comput Aided Mol Des 26:775–786
Sotriffer CA, Krämer O, Klebe G (2004) Proteins Struct Funct Bioinf 56:52–66
Klebe G, Krämer O, Sotriffer CA (2004) CMLS, Cell Mol Life Sci 61:783–793
CrystalExplorer (Version 3.1), Wolff SK, Grimwood DJ, McKinnon JJ, Turner MJ, Jayatilaka D, Spackman MA (2012) University of Western Australia
Gaussian 09, Revision D.01, Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov, VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ, Gaussian, Inc, Wallingford CT, 2013
Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P, Pidcock E, Rodriguez-Monge L, Taylor R, van de Streek J, Wood PA (2007) J Appl Crystallogr 41:466–470
McKinnon JJ, Jayatilaka D, Spackman MA (2007) Chem Commun:3814–3816
Grimme S, Ehrlich S, Goerigk L (2011) J Comput Chem 32:1456–1465
Acknowledgements
We are grateful to the Shiv Nadar University for infrastructure and high-performance computer cluster facility. PM thanks SERB, Govt. of India, for research grant (EMR/2014/000491). SKM thanks UGC for research fellowship. PS thanks Dylan Jayatilaka for the helpful discussion regarding Hirshfeld surfaces for protein–ligand complexes.
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This paper is dedicated to Professor Lou Massa on the occasion of his Festschrift: A Path through Quantum Crystallography.
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Mandal, S.K., Saha, P., Munshi, P. et al. Exploring potent ligand for proteins: insights from knowledge-based scoring functions and molecular interaction energies. Struct Chem 28, 1537–1552 (2017). https://doi.org/10.1007/s11224-017-1007-y
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DOI: https://doi.org/10.1007/s11224-017-1007-y