Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

DFT based Computational Methodology of IC50 Prediction

Author(s): Arijit Bag*

Volume 17, Issue 2, 2021

Published on: 19 February, 2020

Page: [244 - 253] Pages: 10

DOI: 10.2174/1573409916666200219115112

Price: $65

Abstract

Background: IC50 is one of the most important parameters of a drug. But, it is very difficult to predict this value of a new compound without experiment. There are only a few QSAR based methods available for IC50 prediction, which is also highly dependable on a huge number of known data. Thus, there is an immense demand for a sophisticated computational method of IC50 prediction in the field of in silico drug designing.

Objective: Recently developed quantum computation based method of IC50 prediction by Bag and Ghorai requires an affordable known data. In present research work, further development of this method is carried out such that the requisite number of known data being minimal.

Methods: To retrench the cardinal data span and shrink the effects of variant biological parameters on the computed value of IC50, a relative approach of IC50 computation is pursued in the present method. To predict an approximate value of IC50 of a small molecule, only the IC50 of a similar kind of molecule is required for this method.

Results: The present method of IC50 computation is tested for both organic and organometallic compounds as HIV-1 capsid A inhibitor and cancer drugs. Computed results match very well with the experiment.

Conclusion: This method is easily applicable to both organic and organometallic compounds with acceptable accuracy. Since this method requires only the dipole moments of an unknown compound and the reference compound, IC50 based drug search is possible with this method. An algorithm is proposed here for IC50 based drug search.

Keywords: IC50, DFT, RICM, QCM, HIV, computation methodology.

« Previous Next »
Graphical Abstract

[1]
Szilágyi, A.; Závodszky, P. Structural basis for the extreme thermostability of D-glyceraldehyde-3-phosphate dehydrogenase from Thermotoga maritima: analysis based on homology modelling. Protein Eng., 1995, 8(8), 779-789.
[http://dx.doi.org/10.1093/protein/8.8.779] [PMID: 8637847]
[2]
Hansson, T.; Oostenbrink, C.; van Gunsteren, W. Molecular dynamics simulations. Curr. Opin. Struct. Biol., 2002, 12(2), 190-196.
[http://dx.doi.org/10.1016/S0959-440X(02)00308-1] [PMID: 11959496]
[3]
Ciccotti, G.; Ferrario, M. Dynamical non-equilibrium molecular dynamics. Entropy (Basel), 2014, 16(1), 233-257.
[http://dx.doi.org/10.3390/e16010233]
[4]
Binder, K.; Horbach, J.; Kob, W.; Paul, W.; Varnik, F. Molecular dynamics simulations. J. Phys. Condens. Matter, 2004, 16(5), S429.
[http://dx.doi.org/10.1088/0953-8984/16/5/006]
[5]
Ewing, T.J.; Kuntz, I.D. Critical evaluation of search algorithms for automated molecular docking and database screening. J. Comput. Chem., 1997, 18(9), 1175-1189.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19970715)18:9<1175::AID-JCC6>3.0.CO;2-O]
[6]
Shoichet, B.K.; Kuntz, I.D.; Bodian, D.L. Molecular docking using shape descriptors. J. Comput. Chem., 1992, 13(3), 380-397.
[http://dx.doi.org/10.1002/jcc.540130311]
[7]
Gschwend, D.A.; Good, A.C.; Kuntz, I.D. Molecular docking towards drug discovery. J. Mol. Recognit., 1996, 9(2), 175-186.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199603)9:2<175::AID-JMR260>3.0.CO;2-D] [PMID: 8877811]
[8]
Zhang, J.H.; Chung, T.D.; Oldenburg, K.R. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen., 1999, 4(2), 67-73.
[http://dx.doi.org/10.1177/108705719900400206] [PMID: 10838414]
[9]
Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 2009, 138(4), 645-659.
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730]
[10]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110(18), 5959-5967.
[http://dx.doi.org/10.1021/ja00226a005] [PMID: 22148765]
[11]
Seidel, T.; Ibis, G.; Bendix, F.; Wolber, G. Strategies for 3D pharmacophore-based virtual screening. Drug Discov. Today. Technol., 2010, 7(4), e203-e270.
[http://dx.doi.org/10.1016/j.ddtec.2010.11.004] [PMID: 24103798]
[12]
Karelson, M.; Lobanov, V.S.; Katritzky, A.R. Quantum-chemical descriptors in QSAR/QSPR studies. Chem. Rev., 1996, 96(3), 1027-1044.
[http://dx.doi.org/10.1021/cr950202r] [PMID: 11848779]
[13]
Rogers, D.; Hopfinger, A.J. Application of genetic function approximation to quantitative structure-activity relationships and quantitative structure-property relationships. J. Chem. Inf. Comput. Sci., 1994, 34(4), 854-866.
[http://dx.doi.org/10.1021/ci00020a020]
[14]
Bag, A.; Ghorai, P.K. Development of Quantum Chemical Method to Calculate Half Maximal Inhibitory Concentration (IC50). Mol. Inform., 2016, 35(5), 199-206.
[http://dx.doi.org/10.1002/minf.201501004] [PMID: 27492086]
[15]
Bag, A. Theoretical calculation of logp of organometallic clusters of group-8 elements. Int. J. Inno. Pharma. Sci. Res., 2015, 3(10), 1521-1528.
[16]
Zhu, H.; Sedykh, A.; Chakravarti, S.K.; Klopman, G. A new group contribution approach to the calculation of LogP. Curr. Comp. Aided Drug Des., 2005, 1, 3-9.
[http://dx.doi.org/10.2174/1573409052952323]
[17]
Klopman, G.; Li, J.Y.; Wang, S.; Dimayuga, M. Computer automated log P Calculations based on an extended group contribution approach. J. Chem. Inf. Comput. Sci., 1994, 34(4), 752-781.
[http://dx.doi.org/10.1021/ci00020a009]
[18]
Wang, R.; Fu, Y.; Lai, L. A new atom-additive method for calculating partition coefficients. J. Chem. Inf. Comput. Sci., 1997, 37, 615-621.
[http://dx.doi.org/10.1021/ci960169p]
[19]
Bag, A.; Ghorai, P.K. Computational investigation of ligand field effect to improve photoacoustic contrast behavior of organometallic carbonyl clusters. RSC Advances, 2015, 5, 31575-31583.
[http://dx.doi.org/10.1039/C5RA01757B]
[20]
Bag, A.; Ghorai, P.K. Enhancement of biocompatibility and photoacoustic contrast activity of metal clusters. J. Mol. Graph. Model., 2017, 75, 220-232.
[http://dx.doi.org/10.1016/j.jmgm.2017.05.011] [PMID: 28601707]
[21]
Sharma, N.; Ethiraj, K.R.; Yadav, M.; Nayarisseri, S. A.; Chaurasiya, M.; Vankudavath, R.N.; Rao, K.R. Identification of LOGP values and Electronegativities as structural insights to model inhibitory activity of HIV-1 capsid inhibitors - a SVM and MLR aided QSAR studies. Curr. Top. Med. Chem., 2012, 12(16), 1763-1774.
[http://dx.doi.org/10.2174/1568026611209061763] [PMID: 23030611]
[22]
Cristianini, N.; Shawe-Taylor, J. An introduction to support Vector Machines: and other kernel-based learning methods; Cambridge University Press: New York, NY, USA, 2000.
[http://dx.doi.org/10.1017/CBO9780511801389]
[23]
Parr, R.G. Szentp疝y, L. v.; Liu, S. Electrophilicity index. J. Am. Chem. Soc., 1999, 121(9), 1922-1924.
[http://dx.doi.org/10.1021/ja983494x]
[24]
Chatterjee, S.; Kundu, S.; Bhattacharyya, A.; Hartinger, C.G.; Dyson, P.J. The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways. J. Biol. Inorg. Chem., 2008, 13(7), 1149-1155.
[http://dx.doi.org/10.1007/s00775-008-0400-9] [PMID: 18597125]
[25]
Parr, R.G.; Pearson, R.G. Absolute hardness: companion parameter to absolute electronegativity. J. Am. Chem. Soc., 1983, 105, 7512-7516.
[http://dx.doi.org/10.1021/ja00364a005]
[26]
Nakamura, Y.; Higaki, T.; Kato, H.; Kishida, F.; Kogiso, S.; Isobe, N.; Kaneko, H. A quantitative comparison of induction and challenge concentrations inducing a 50% positive response in three skin sensitization tests; the guinea pig maximization test, adjuvant and patch test and Buehler test. J. Toxicol. Sci., 1999, 24(2), 123-131.
[http://dx.doi.org/10.2131/jts.24.123] [PMID: 10349614]
[27]
Hohenberg, P.; Kohn, W. Inhomogeneous electron gas. Phys. Rev., 1964, 136(3B), B864.
[http://dx.doi.org/10.1103/PhysRev.136.B864]
[28]
Kohn, W.; Becke, A.D.; Parr, R.G. Density functional theory of electronic structure. J. Phys. Chem., 1996, 100(31), 12974-12980.
[http://dx.doi.org/10.1021/jp960669l]
[29]
Geertsen, J.; Rittby, M.; Bartlett, R.J. The equation-of-motion coupled-cluster method: Excitation energies of Be and CO. Chem. Phys. Lett., 1989, 164(1), 57-62.
[http://dx.doi.org/10.1016/0009-2614(89)85202-9]
[30]
Stanton, J.F.; Bartlett, R.J. The equation of motion coupled cluster A R cluster method. A systematic biorthogonal approach to molecular excitation energies, transition probabilities, and excited state properties. J. Chem. Phys., 1993, 98(9), 7029-7039.
[http://dx.doi.org/10.1063/1.464746]
[31]
Bag, A.; Manohar, P.U.; Vaval, N.; Pal, S. First- and second-order electrical properties computed at the FSMRCCSD level for excited states of closed-shell molecules using the constrained-variational approach. J. Chem. Phys., 2009, 131(2)024102
[http://dx.doi.org/10.1063/1.3167796] [PMID: 19603965]
[32]
Chowdhury, U.D.; Bag, A. Excited state hyperpolarizability of LiAlH4 computed at the FSMRCCSD level and its use for mixed-frequency laser. Theor. Chem. Acc, 2018, 137(2), 23.1-23.11.
[http://dx.doi.org/10.1007/s00214-018-2203-6]
[33]
Bag, A.; Manohar, P.U.; Pal, S. Analytical dipole moments and dipole polarizabilities of oxygen mono-fluoride and nitrogen dioxide: A constrained variational response to fock-space multi-reference coupled-cluster method. Comput. Lett., 2007, 3(2-4), 351-358.
[http://dx.doi.org/10.1163/157404007782913381]
[34]
Bag, A. Transition probability approach for direct calculation of coefficients of configuration interaction wave function. Curr. Sci., 2017, 113, 2325-2328.
[http://dx.doi.org/10.18520/cs/v113/i12/2325-2328]
[35]
Gaussian, Inc. Wallingford CT, 2009.
[36]
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[http://dx.doi.org/10.1103/PhysRevA.38.3098] [PMID: 9900728]
[37]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[38]
Perdew, J.P. Electronic Structure of Solids; Ziesche, P; Eschrig, H., Ed.; Akademie Verlag: Berlin, 1991, p. 11.
[39]
Perdew, J.P.; Chevary, J.A.; Vosko, S.H.; Jackson, K.A.; Pederson, M.R.; Singh, D.J.; Fiolhais, C. Atoms, molecules, solids, and surfaces: Applications of the generalized gradient approximation for exchange and correlation. Phys. Rev. B Condens. Matter, 1992, 46(11), 6671-6687.
[http://dx.doi.org/10.1103/PhysRevB.46.6671] [PMID: 10002368]
[40]
Perdew, J.P.; Chevary, J.A.; Vosko, S.H.; Jackson, K.A.; Pederson, M.R.; Singh, D.J.; Fiolhais, C. Erratum: Atoms, molecules, solids, and surfaces: applications of the generalized gradient approximation for exchange and correlation. Phys. Rev. B Condens. Matter, 1993, 48(7), 4978.
[http://dx.doi.org/10.1103/PhysRevB.48.4978.2] [PMID: 10021600]
[41]
Perdew, J.P.; Burke, K.; Wang, Y. Generalized gradient approximation for the exchange-correlation hole of a many-electron system. Phys. Rev. B Condens. Matter, 1996, 54(23), 16533-16539.
[http://dx.doi.org/10.1103/PhysRevB.54.16533] [PMID: 9985776]
[42]
Hay, P.J.; Wadt, W.R. Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. J. Chem. Phys., 1985, 82, 270-283.
[http://dx.doi.org/10.1063/1.448799]
[43]
Wadt, W.R.; Hay, P.J. Ab initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi. J. Chem. Phys., 1985, 82, 284-298.
[http://dx.doi.org/10.1063/1.448800]
[44]
Hay, P.J.; Wadt, W.R. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys., 1985, 82, 299-310.
[http://dx.doi.org/10.1063/1.448975]
[45]
Bag, A. Application of glucose modified bicyclophosphite derivative of tri-ruthenium carbonyl cluster as advanced photo acoustic contrast agent. Saudi J. Med. Pharm. Sci, 2015, 1(3), 80-82.
[46]
Bag, A. TB drug potency of a structure modified derivative of ethambutol: a docking based and quantum-chemical comparison study. Adv. Biores., 2016, 7(2), 93-99.
[47]
Ishihara, M.; Kawase, M.; Westman, G.; Samuelsson, K.; Motohashi, N.; Sakagami, H. Quantitative structure-cytotoxicity relationship analysis of phenoxazine derivatives by semiempirical molecular-orbital method. Anticancer Res., 2007, 27(6B), 4053-4057.
[PMID: 18225570]
[48]
Bikadi, Z.; Hazai, E. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J. Chem. Phys., 2009, 82, 299-310.
[http://dx.doi.org/10.1186/1758-2946-1-15]
[49]
Huey, R.; Morris, G.M.; Olson, A.J.; Goodsell, D.S. A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem., 2007, 28(6), 1145-1152.
[http://dx.doi.org/10.1002/jcc.20634] [PMID: 17274016]
[50]
Monaco-Malbet, S.; Berthet-Colominas, C.; Novelli, A.; Battaï, N.; Piga, N.; Cheynet, V.; Mallet, F.; Cusack, S. Mutual conformational adaptations in antigen and antibody upon complex formation between an Fab and HIV-1 capsid protein p24. Structure, 2000, 8(10), 1069-1077.
[http://dx.doi.org/10.1016/S0969-2126(00)00507-4] [PMID: 11080628]
[51]
Christopher, T.L.; Steve, T. Uta von S.; Nathalie G.; Mercier, J. F.; Wardrop, E.; Faucher, A. M.; Coulombe, R.; Soma, S.; Banik, R.; Fader, L.; Gagnon, A.; Stephen H. Kawai, Jean Rancourt, Martin Tremblay, Christiane Yoakim, Bruno Simoneau, Jacques Archambault, Wesley I. Sundquist, Stephen W. Mason Distinct Effects of Two HIV-1 Capsid Assembly Inhibitor Families That Bind the Same Site within the N-Terminal Domain of the Viral CA Protein. J. Virol., 2012, 86, 6643-6655.
[52]
Nazarov, A.A.; Baquié, M.; Nowak-Sliwinska, P.; Zava, O.; van Beijnum, J.R.; Groessl, M.; Chisholm, D.M.; Ahmadi, Z.; McIndoe, J.S.; Griffioen, A.W.; van den Bergh, H.; Dyson, P.J. Synthesis and characterization of a new class of anti-angiogenic agents based on ruthenium clusters. Sci. Rep., 2013, 3, 1485.
[http://dx.doi.org/10.1038/srep01485] [PMID: 23508096]
[53]
Kong, K.V.; Leong, W.K.; Ng, S.P.; Nguyen, T.H.; Lim, L.H.K. Osmium carbonyl clusters: a new class of apoptosis inducing agents. ChemMedChem, 2008, 3(8), 1269-1275.
[http://dx.doi.org/10.1002/cmdc.200800069] [PMID: 18433076]

Rights & Permissions Print Cite
Article Metrics
66
2
© 2024 Bentham Science Publishers | Privacy Policy