Determining chemical reactivity driving biological activity from SMILES transformations: The bonding mechanism of anti-HIV pyrimidines

Molecules

Volumn 18, Issue 8, 2013, Pages 9061-9116

  Putz, Mihai V ^a   Dudaş, Nicoleta A ^a  

^a WEST UNIVERSITY OF TIMISOARA   (Romania)

Author keywords

1,3 disubstituted uracil derivatives; Anti HIV activity; Chemical hardness; Chemical power; Chemical reactivity principles; Electronegativity; Electrophilicity; Lipophilicity; QSAR; SMILES

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DRUG DERIVATIVE; URACIL;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER PROGRAM; DRUG EFFECT; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MONTE CARLO METHOD; PATHOLOGY; QUANTITATIVE STRUCTURE ACTIVITY RELATION; ANALOGS AND DERIVATIVES; DRUG EFFECTS; HIV INFECTIONS;

ANTI-HIV AGENTS; HIV INFECTIONS; HIV-1; HUMANS; MOLECULAR STRUCTURE; MONTE CARLO METHOD; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; SOFTWARE; URACIL;

EID: 84883181757     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules18089061     Document Type: Article

References (177)

1. Péry, A.R.R.; Brochot, C.; Zeman, F.A.; Mombelli, E.; Desmots, S.; Pavan, M.; Fioravanzo, E.; Zaldivar, J.M. Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: A case study with acetaminophen. Toxicol. Lett. 2013, 220, 26-34.
2. Diaz Ochoa, J.G.; Bucher, J.; Péry, A.R.R.; Zaldivar, J.M.; Niclas, J.; Mauch, K. A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk. Front. Pharmacol. 2013, 3, 204.
3. Worth, A.P.; Lapenna, S.; Serafimova, R. QSAR and metabolic assessment tools in the assessment of genotoxicity. Method. Mol. Biol. 2012, 930, 125-162.
4. Tonnelier, A.; Coecke, S.; Zaldivar, J.M. Screening of chemicals for human bioaccumulative potential with a physiologically based toxicokinetic model. Arch. Toxicol. 2012, 86, 393-403.
5. Burello, E.; Worth, A.P. QSAR modeling of nanomaterials. WIREs Nanomed. Nanobiotechnol. 2011, 3, 298-306.
6. Burello, E.; Worth, A.P. A theoretical framework for predicting the oxidative stress potential of oxide nanoparticles. Nanotoxicology 2011, 5, 228-235.
7. Burello, E.; Worth, A.P. Computational nanotoxicology: Predicting toxicity of nanoparticles. Nat. Nanotechnol. 2011, 6, 138-139.
8. Lo Piparo, E.; Worth, A.; Manibusan, M.; Yang, C.; Schilter, B.; Mazzatorta, P.; Jacobs, M.N.; Steinkellner, H.; Mohimont, L. Use of computational tools in the field of food safety. Regul. Toxicol. Pharm. 2011, 60, 354-362.
9. Raevsky, O.A.; Liplavskaya, E.A.; Yarkova, A.V.; Raevskaya, O.E.; Worth, A.P. Linear and nonlinear QSAR models of acute intravenous toxicity of organic chemicals for mice. Biochem. (Moscow) Suppl. Ser. B Biomed. Chem. 2011, 5, 213-225.
10. Worth, A.P.; Mostrag-Szlichtyng, A. Towards a common regulatory framework for computational toxicology: current status and future perspectives. In New Horizons in Predictive Toxicology: Methods and Applications; Wilson, A.G.E., Ed.; The Royal Society of Chemistry: Cambridge, UK, 2011; pp. 38-69.
11. Mostrag-Szlichtyng, A.; Zaldivar, J.M.; Worth, A.P. Computational toxicology at the European Commission's Joint Research Centre. Expert Opin. Drug Met. 2010, 6, 785-792.
12. Novellino, A.; Zaldivar, J.M. Recurrence quantification analysis of spontaneous electrophysiological activity during development: Characterization of in vitro neuronal networks cultured on multi electrode array chips. Adv. Artificial Intelligence 2010, 2010, doi:10.1155/2010/209254.
13. Raevsky, O.A.; Grigor'ev, V.J.; Modina, E.A.; Worth, A.P. Prediction of acute toxicity to mice by the Arithmetic Mean Toxicity (AMT) modelling approach. SAR QSAR Environ. Res. 2010, 21, 265-275.
14. Bacelar, F.S.; Dueri, S.; Hernandez-Garcia, E.; Zaldivar, J.M. Joint effects of nutrients and contaminants on the dynamics of a food chain in marine ecosystems. Math. Biosci. 2009, 218, 24-32.
15. Poater, A.; Gallegos, A.; Sola, M.; Cavallo, L.; Worth, A.P. Computational methods to predict the reactivity of nanoparticles through structure-property relationships. Expert Opin. Drug Del. 2009, 7, 1-11.
16. Poater, A.; Gallegos, A.; Carbo-Dorca, R.; Poater, J.; Sola, M.; Cavallo, L.; Worth, A.P. Modeling the structure-property relationships of nanoneedles: A journey toward nanomedicine. J. Comput. Chem. 2009, 30, 275-284.
17. Bassan, A.; Worth, A.P. The integrated use of models for the properties and effects of chemicals by means of a structured workflow. QSAR Comb. Sci. 2008, 27, 6-20.
18. Kahn, I.; Maran, U.; Benfenati, E.; Netzeva, T.I.; Schultz, T.W.; Cronin, M.T.D. Comparative quantitative structure-activity-activity relationships for toxicity to Tetrahymena pyriformis and Pimephales promelas. Altern. Lab. Anim. ATLA 2007, 35, 15-24.
19. Gallegos, A. Mini-review on chemical similarity and prediction of toxicity. Curr. Comp.-Aid. Drug. 2006, 2, 105-122.
20. Patlewicz, G. Computational methods to predict drug safety. Curr. Comp.-Aid. Drug. 2006, 2, 151-168.
21. Dimitrov, S.; Dimitrova, G.; Pavlov, T.; Dimitrova, N.; Patlewicz, G.; Niemela, J.; Mekenyan, O. A stepwise approach for defining the applicability domain of SAR and QSAR models. J. Chem. Inf. Model. 2005, 45, 839-849.
22. Gallegos, A.; Carbó-Dorca, R.; Lodier, F.; Cancès, E.; Savin, A. Maximal probability domains in linear molecules. J. Comput. Chem. 2005, 26, 455-460.
23. Gallegos, A.; Gironés, X. Topological quantum similarity indices based on fitted densities: Theoretical background and QSPR application. J. Chem. Inf. Model. 2005, 45, 321-326.
24. Gallegos, A.; Gironés, X. Topological quantum similarity measures: Applications in QSAR. J. Mol. Struct. (THEOCHEM) 2005, 727, 97-106.
25. Netzeva, T.I.; Aptula, A.O.; Benfenati, E.; Cronin, M.T.D.; Gini, G.; Lessigiarska, I.; Maran, U.; Vracko, M.; Schuurmann, G. Description of the electronic structure of organic chemicals using semiempirical and ab initio methods for development of toxicological QSARs. J. Chem. Inf. Model. 2005, 45, 106-114.
26. Ponec, R.; Bultinck, P.; Gallegos, A. Multicenter bond indices as a new means for the quantitative characterization of homoaromaticity. J. Phys. Chem. A 2005, 109, 6606-6609.
27. Schultz, T.W.; Netzeva, T.I.; Roberts, D.W.; Cronin, M.T.D. Structure-Toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, α,β-carbonyl-containing, unsaturated chemicals. Chem. Res. Toxicol. 2005, 18, 330-341.
28. Lessigiarska, I.; Worth, A.P.; Sokull-Klüttgen, B.; Jeram, S.; Dearden, J.C.; Netzeva, T.I.; Cronin, M.T.D. QSAR investigation of a large data set for fish, algae and Daphnia toxicity. SAR QSAR Environ. Res. 2004, 15, 413-431.
29. Cronin, M.T.D.; Dearden, J.C.; Walker, J.D.; Worth, A.P. Quantitative structure-activity relationships for human health effects: Commonalities with other endpoints. Environ. Toxicol. Chem. 2003, 22, 1829-1843.
30. Worth, A.P.; Cronin, M.T.D. The use of discriminant analysis, logistic regression and classification tree analysis in the development of classification models for human health effects. J. Mol. Struct. (Theochem) 2003, 622, 97-111.
31. Cronin, M.T.D.; Dearden, J.C.; Duffy, J.C.; Edwards, R.; Manga, N.; Worth, A.P.; Worgan, A.D.P. The importance of hydrophobicity and electrophilicity descriptors in mechanisticallybased QSARs for toxicological endpoints. SAR QSAR Environ. Res. 2002, 13, 167-176.
32. Cronin, M.T.D.; Aptula, A.O.; Dearden, J.C.; Duffy, J.C.; Netzeva, T.I.; Patel, H.; Rowe, P.H.; Schultz, T.W.; Worth, A.P.; Voutzoulidis, K.; et al. Structure-based classification of antibacterial activity. J. Chem. Inf. Comp. Sci. 2002, 42, 869-878.
33. Worth, A.P.; van Leeuwen, C.J.; Hartung, T. The prospects for using (Q)SARs in a changing political environment - high expectations and a key role for the Commission's Joint Research Centre. SAR QSAR Environ. Res. 2004, 15, 331-343.
34. Worth, A.P.; Cronin, M.T.D.; van Leeuwen, C.J. A framework for promoting the acceptance and regulatory use of (Quantitative) Structure-Activity Relationships. In Predicting Chemical Toxicity and Fate; Cronin, M.T.D., Livingstone, D., Eds.; CRC Press: Boca Raton, FL, USA, 2004; pp. 427-438.
35. OECD. Report from the Expert Group on (Quantitative) Structure-Activity Relationships [(Q)SARs] on the Principles for the Validation of (Q)SARs, Series on Testing and Assessment, No. 49. OECD: Paris, France, 2004. Available online: http://www.oecd.org/document/30/0,2340,en-2649-34365-1916638-1-1-1-1,00.html (accessed on 3 March 2011).
36. OECD. Guidance Document on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment, Series on Testing and Assessment, No. 34. OECD: Paris, France, 2005. Available online: http://www.oecd.org/document/30/0,2340,en-2649-34365-1916638-1-1-1-1, 00.html (accessed on 3 March 2011).
37. OECD. Report on the Regulatory Uses and Applications in OECD Member Countries of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models in the Assessment of New and Existing Chemicals, Series on Testing and Assessment, No. 58. OECD: Paris, France, 2006. Available online: http://www.oecd.org/ document/30/0,2340,en-2649-34365-1916638-1-1-1-1,00.html (accessed on 3 March 2011).
38. OECD Guidance Document on the Validation of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models, Series on Testing and Assessment, No. 69, OECD, Paris, France, 2006; p. 154. Available online: http://www.oecd.org/document/30/0,2340,en-2649-34365-1916638-1-1-1-1,00.html (accessed on 3 March 2011).
39. Patlewicz, G.; Jeliazkova, N.; Gallegos, A.; Worth, A.P. Toxmatch - A new software tool to aid in the development and evaluation of chemically similar groups. SAR QSAR Environ. Res. 2008, 19, 397-412.
40. Todeschini, R.; Ballabio, D.; Consonni, V.; Mauri, A.; Pavan, M. CAIMAN (Classification And Influence Matrix Analysis): A new approach to the classification based on leverage-scaled functions. Chemom. Intell. Lab. 2007, 87, 3-17.
41. Patlewicz, G.; Jeliazkova, N.; Safford, R.J.; Worth, A.P.; Aleksiev, B. An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR QSAR Environ. Res. 2008, 19, 495-524.
42. Gallegos, A.; Poater, A.; Jeliazkova, N.; Patlewicz, G.; Worth, A.P. Toxmatch - A chemical classification and activity prediction tool based on similarity measures. Regul. Toxicol. Pharm. 2008, 52, 77-84.
43. Patlewicz, G.; Aptula, A.O.; Uriarte, E.; Roberts, D.W.; Kern, P.S.; Gerberick, G.F.; Kimber, I.; Dearman, R.J.; Ryan, C.A.; Basketter, D.A. An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential. SAR QSAR Environ. Res. 2007, 18, 515-541.
44. Jaworska, J; Nikolova-Jeliazkova, N; Aldenberg, T. QSAR applicability domain estimation by projection of the training set descriptor space: a review. Altern. Lab. Anim. 2005, 33, 445-459.
45. Jeliazkova, N.; Jaworska, J.; Worth, A.P. Open source tools for read across and category formation, In In Silico Toxicology. Principles and Applications; Cronin, M.T.D., Madden, J., Eds.; Royal Society of Chemistry: Cambridge, UK, 2010; pp. 408-445.
46. Pavan, M.; Todeschini, R. Multi-criteria decision making methods. In Comprehensive Chemometrics; Brown, S., Walczak, B., Tauler, R., Eds.; Elsevier: Amsterdam, The Netherlands, 2009; Volume 1, pp. 591-629.
47. Pavan, M., Todeschini, R. Eds. Scientific data ranking methods: theory and applications. Data handling. In Science and Technology, 1st ed; Elsevier: Oxford, UK, 2008; Volume 27.
48. Roberts, D.W.; Aptula, A.O.; Patlewicz, G.; Pease, C. Chemical reactivity indices and mechanism-based read-across for non-animal based assessment of skin sensitisation potential. J. Appl. Toxicol. 2008, 28, 443-454.
49. Spycher, S.; Netzeva, T.I.; Worth, A.P.; Escher, B.I. Mode of action-based classification and prediction of activity of uncouplers for the screening of chemical inventories. SAR QSAR Environ. Res. 2008, 19, 433-463.
50. Benigni, R.; Bossa, C.; Netzeva, T.I.; Rodomonte, A.; Tsakovska, I. Mechanistic QSAR of aromatic amines: New models for discriminating between homocyclic mutagens and nonmutagens, and validation of models for carcinogens. Environ. Mol. Mutagen. 2007, 48, 754-771.
51. Vracko, M.; Bandelj, V.; Barbieri, P.; Benfenati, E.; Chaudhry, Q.; Cronin, M.T.D.; Devillers, J.; Gallegos, A.; Gini, G.; Gramatica, P.; et al. Validation of counter propagation neural network models for predictive toxicology according to the OECD principles: A case study. SAR QSAR Environ. Res. 2006, 17, 265-284.
52. Dirac, P.A.M. The Principles of Quantum Mechanics, 2nd ed.; Clarendon Press: Oxford, UK, 1947.
53. Putz, M.V., Ed.; QSAR & SPECTRAL-SAR in Computational Ecotoxicology; Apple Academics: Ontario, Canada, 2012.
54. Putz, M.V. Chemical orthogonal spaces; Mathematical Chemistry Monographs; Publisher: Kragujevac, Serbia, 2012; Volume 14.
55. Putz, M.V. Chemical Orthogonal Spaces (COSs): From structure to reactivity to biological activity. Int. J. Chem. Model. 2013, 5, in press.
56. Putz, M.V.; Putz, A.M.; Lazea, M.; Ienciu, L.; Chiriac, A. Quantum-SAR extension of the Spectral-SAR algorithm. Application to polyphenolic anticancer bioactivity. Int. J. Mol. Sci. 2009, 10, 1193-1214.
57. Putz, M.V.; Lacrǎmǎ, A.M. Introducing spectral structure activity relationship (S-SAR) Analysis. application to ecotoxicology. Int. J. Mol. Sci. 2007, 8, 363-391.
58. Putz, M.V.; Putz, A.M. Timisoara Spectral-Structure Activity Relationship (Spectral-SAR) Algorithm: From statistical and algebraic fundamentals to quantum consequences. In Quantum Frontiers of Atoms and Molecules; "Series, Chemistry Research and Applications"; Putz, M.V., Ed.; NOVA Science Publishers, Inc.: New York, NY, USA, 2011; pp. 539-580.
59. Putz, M.V.; Putz, A.M. DFT chemical reactivity driven by biological activity: Applications for the toxicological fate of chlorinated PAHs. Struct. Bond. 2013, 150, 181-232.
60. Putz, M.V.; Putz, A.M.; Lazea, M.; Chiriac, A. Spectral vs. statistic approach of Structure-Activity Relationship. Application on ecotoxicity of aliphatic amines. J. Theor. Comput. Chem. 2009, 8, 1235-1251.
61. Lacrǎmǎ, A.M.; Putz, M.V.; Ostafe, V. A Spectral-SAR model for the anionic-cationic interaction in ionic liquids: application to Vibrio fischeri ecotoxicity. Int. J. Mol. Sci. 2007, 8, 842-863.
62. Putz, M.V.; Lacrǎmǎ, A.M.; Ostafe, V. Spectral-SAR ecotoxicology of ionic liquids. The Daphnia magna Case. Int. J. Ecology (former Res. Lett. Ecology) 2007, 2007, doi:10.1155/2007/12813.
63. Putz, M.V.; Putz, A.M.; Ostafe, V.; Chiriac, A. Spectral-SAR Ecotoxicology of Ionic Liquids-Acetylcholine Interaction on E. Electricus Species. Int. J. Chem. Model. 2010, 2, 85-96.
64. Putz, M.V.; Dudaş; N.A. Variational principles for mechanistic quantitative structure-activity relationship (QSAR) studies: Application on uracil derivatives' anti-HIV action. Struct. Chem., 2013, DOI 10.1007/s11224-013-0249-6.
65. Weininger, D. SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J. Chem. Inf. Model. 1988, 28, 31-36.
66. Weininger, D.; Weininger, A.; Weininger, J.L. SMILES. 2. Algorithm for generation of unique SMILES notation. J. Chem. Inf. Model. 1989, 29, 97-101.
67. Weininger, D. SMILES. 3. DEPICT. Graphical depiction of chemical structures. J. Chem. Inf. Model. 1990, 30, 237-243.
68. Helson, H.E. Structure Diagram Generation. In Reviews in Computational Chemistry; Lipkowitz, K.B., Boyd, D.B., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2007; Volume 13, pp. 313-398.
69. Maruyama, T.; Kozai, S.; Yamasaki, T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; Snoeck, R.; Andrei G.; De Clercq E. Synthesis and antiviral activity of 1,3-disubstituted uracils against HIV-1 and HCMV Antivir. Chem.Chemoth. 2003, 14, 271-279..
70. Putz, M.V.; Putz, A.M.; Barou, R. Spectral-SAR realization of OECD-QSAR principles. Int. J. Chem. Model. 2011, 3, 173-190.
71. +-ATPase inhibitory activity. Int. J. Chem. Model. 2008, 1, 45-62.
72. Garg, R.; Gupta, S.P.; Gao, H.; Babu, M.S.; Debnath, A.K.; Hansch, C. QSAR studies on anti HIV-1 drugs. Chem. Rev. 1999, 99, 3525-3601.
73. Mehellou, Y.; De Clercq E. Twenty-six years of anti-HIV drug discovery: Where do we stand and where do we go? J. Med. Chem. 2010, 53, 521-538.
74. Esposito, F.; Corona, A.; Tramontano, E. HIV-1 reverse transcriptase still remains a new drug target: structure, function, classical inhibitors, and new inhibitors with innovative mechanisms of actions. Mol. Biol. Int. 2012, 2012, doi:10.1155/2012/586401.
75. Quashie, P.K.; Sloan, R.D.; Wainberg, M.A. Novel therapeutic strategies targeting HIV integrase. BMC Medicine 2012, 10, 34.
76. Kaufmann, G.R.; Cooper, D.A. Antiretroviral therapy of HIV-1 infection: established treatment strategies and new therapeutic options. Curr. Opin. Microbiol. 2000, 3, 508-5144
77. De Clercq, E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int. J. of Antimicrob. Agents 2009, 33, 307-320.
78. Krausslich, H.G., Bartenschlager, R., Eds. Antiviral strategies. In Handbook of Experimental Pharmacology; Springer-Verlag: Berlin-Heidelberg, Germany, 2010; Volume 189.
79. Benigni, R.; Netzeva, T.I.; Benfenati, E.; Bossa, C.; Franke, R.; Helma, C.; Hulzebos, E.; Marchant, C.; Richard, A.; Woo, Y.T.; et al. The expanding role of predictive toxicology: An update on the (Q)SAR models for mutagens and carcinogens. J. Environ. Sci. Health C 2007, 25, 53-97.
80. Benigni, R.; Bossa, C.; Jeliazkova, N.; Netzeva, T.; Worth, A. The Benigni/Bossa Rules for Mutagenicity and CarcInogenicity - A Module of Toxtree; European Commission report EUR 23241 EN; IdeaConsult Ltd.: Sofia, Bulgaria, 2008. Available online: http://toxtree.sourceforge.net/carc.html (accessed on 3 August 2011).
81. Lessigiariska, I.; Worth, A.P.; Cronin, M.T.D. Structure-Activity Relationships for Pharmacotoxicological Endpoints; Lambert Academic Publishing: Saarbrucken, Germany, 2010.
82. Putz, M.V. Residual-QSAR. Implications for Genotoxic Carcinogenesis. Chem. Cent. J. 2011, 5, 29-40.
83. Tarko, L.; Putz, M.V. On Quantitative Structure-Toxicity Relationships (QSTR) using high chemical diversity molecules group. J. Theor. Comput. Chem., 2012, 11, 265-272.
84. Chemical Identifier Resolver beta 4. Available online: http://cactus.nci.nih.gov/chemical/structure (accessed on 23 February 2013).
85. Moldoveanu, C.C.; Jones, P.G.; Mangalagiu, I.I. Spiroheterocyclic compounds: Old stories with new outcomes. Tetrahedron Lett. 2009, 50, 7205-7208.
86. Gammon, D.B.; Snoeck, R.; Fiten, P.; Krecmerova, M.; Holy, A.; De Clercq, E.; Opdenakker, G.; Evans, D.H.; Andrei, G. Mechanism of antiviral drug resistance of Vaccinia virus: Identification of residues in the viral DNA polymerase conferring differential resistance to Antipoxvirus drugs. J. Virol. 2008, 82, 12520-12534.
87. Fan, S.Y.; Zheng, Z.B.; Mi, C.L.; Zhou, X.B.; Yan, H.; Gong, Z.H.; Li, S. Synthesis and evaluation of novel chloropyridazine derivatives as potent human rhinovirus (HRV) capsid-binding inhibitors. Bioorg. Med. Chem. 2009, 17, 621-624.
88. De Clercq, E. New approaches toward anti-HIV chemotherapy. J. Med. Chem. 2005, 48, 1297-1313.
89. Muhanji, C.I.; Hunter, R. Current developments in the synthesis and biological activity of HIV-1 double-drug inhibitors. Curr. Med. Chem. 2007, 14, 1207-1222.
90. Butnariu, R.; Mangalagiu, I.I. New pyridazine derivatives: Synthesis, Chemistry and biological activity. Bioorg. Med. Chem. 2009, 17, 2823-2829.
91. Balan, A.M.; Florea, O.; Moldoveanu, C.; Zbancioc, G.; Iurea, D.; Mangalagiu, I.I. Diazinium salts with dihydroxyacetophenone skeleton: syntheses and antimicrobial activity. Eur. J. Med. Chem. 2009, 44, 2275-2279.
92. Butnariu, R.; Caprosu, M.; Bejan, V.; Ungureanu, M.; Poiata, A.; Tuchilus, C.; Florescu, M.; Mangalagiu, I.I. Pyridazine and phthalazine derivatives with potential antimicrobial activity. J. Heterocycl. Chem. 2007, 44, 1149-1152.
93. Parr, R.G.; Yang, W. Density-Functional Theory Of Atoms And Molecules; Oxford University Press: New York, NY, USA, 1989.
94. Koopmans, T. Uber die Zuordnung von Wellen Funktionen und Eigenwerter zu den einzelnen Elektronen eines Atom. Physica 1934, 1, 104-113.
95. Parr, R.G.; Donnelly, R.A.; Levy, M.; Palke, W.E. Electronegativity: The density functional viewpoint. J. Chem. Phys. 1978, 68, 3801-3808.
96. Mortier, W.J.; Genechten, K.V.; Gasteiger, J. Electronegativity equalization: Application and parametrization. J. Am. Chem. Soc. 1985, 107, 829-835.
97. Sanderson, R.T. Principles of electronegativity Part I. General nature. J. Chem. Edu. 1988, 65, 112-119.
98. Putz, M.V. Chemical action concept and principle. MATCH Commun. Math. Comput. Chem. 2011, 66, 35-63.
99. Tachibana, A. Density functional rationale of chemical reaction coordinate. Int. J. Quantum Chem. 1987, 21, 181-190.
100. Tachibana, A.; Parr, R.G. On the redistribution of electrons for chemical reaction systems. Int. J. Quantum. Chem. 1992, 41, 527-555.
101. + system. Int. J. Quantum Chem. 1999, 74, 669-679.
102. Parr, R.G.; Yang, W. Density functional approach to the frontier electron theory of chemical reactivity. J. Am. Chem. Soc. 1984, 106, 4049-4050.
103. Yang, W.; Parr, R.G.; Pucci, R. Electron density, Kohn-Sham frontier orbitals, and Fukui functions. J. Chem. Phys. 1984, 81, 2862-2863.
104. Putz, M.V. Contributions within Density Functional Theory with Applications in Chemical Reactivity Theory and Electronegativity; Dissertation.com: Parkland, FL, USA, 2003.
105. Pearson, R.G. Chemical Hardness; Wiley-VCH: Weinheim, Germany, 1997.
106. Putz, M.V. Electronegativity and chemical hardness: different patterns in quantum chemistry. Curr. Phys. Chem. 2011, 1, 111-139.
107. Putz, M.V. Electronegativity: Quantum observable. Int. J. Quantum Chem. 2009, 109, 733-738.
108. Putz, M.V. Chemical hardness: Quantum observable? Studia Univ. Babeş-Bolyai-Ser. Chem. 2010, 55, 47-50.
109. Chattaraj, P.K.; Schleyer, P.V.R. An ab initio study resulting in a greater understanding of the HSAB principle. J. Am. Chem. Soc. 1994, 116, 1067-1071.
110. Chattaraj, P.K.; Maiti, B. HSAB principle applied to the time evolution of chemical reactions. J. Am. Chem. Soc. 2003, 125, 2705-2710.
111. Putz, M.V.; Russo, N.; Sicilia, E. On the application of the HSAB principle through the use of improved computational schemes for chemical hardness evaluation. J. Comput. Chem. 2004, 25, 994-1003.
112. Pearson, R.G. Hard and soft acids and bases - the evolution of a chemical concept. Coord. Chem. Rev. 1990, 100, 403-425.
113. Pearson, R.G. Absolute electronegativity and absolute hardness of Lewis acids and bases. J. Am. Chem. Soc. 1985, 107, 6801-6806.
114. Chattaraj, P.K.; Lee, H.; Parr, R.G. Principle of maximum hardness. J. Am. Chem. Soc. 1991, 113, 1854-1855.
115. Chattaraj, P.K.; Liu, G.H.; Parr, R.G. The maximum hardness principle in the Gyftpoulos-Hatsopoulos three-level model for an atomic or molecular species and its positive and negative ions. Chem. Phys. Lett. 1995, 237, 171-176.
116. Putz, M.V. Maximum hardness index of quantum acid-base bonding. MATCH Commun. Math. Comput. Chem. 2008, 60, 845-868.
117. Ayers, P.W.; Parr, R.G. Variational principles for describing chemical reactions: The Fukui function and chemical hardness revisited. J. Am. Chem. Soc. 2000, 122, 2010-2018.
118. Mineva, T.; Sicilia, E.; Russo, N. Density functional approach to hardness evaluation and its use in the study of the maximum hardness principle. J. Am. Chem. Soc. 1998, 120, 9053-9058.
119. Torrent-Sucarrat, M.; Solà, M. Gas-phase structures, rotational barriers, and conformational properties of hydroxyl and mercapto derivatives of cyclohexa-2,5-dienone and cyclohexa-2,5-dienthione. J. Phys. Chem. A 2006, 110, 8901-8911.
120. Parr, R.G.; Szentpaly, L.V.; Liu, S. Electrophilicity Index. J. Am. Chem. Soc. 1999, 121, 1922-1924.
121. Pérez, P.; Toro-Labbé, A.; Aizman, A.; Contreras, R. Comparison between experimental and theoretical scales of electrophilicity in benzhydryl cations. J. Org. Chem. 2002, 67, 4747-2752.
122. Chamorro, E.; Chattaraj, P.K.; Fuentealba, P. Variation of the electrophilicity index along the reaction path. J. Phys. Chem. A 2003, 107, 7068-7072.
123. Parthasarathi, R.; Elango, M.; Subramanian, V.; Chattaraj, P.K. Variation of electrophilicity during molecular vibrations and internal rotations. Theor. Chem. Acc. 2005, 113, 257-266.
124. Domingo, L.R.; Asensio, A.; Arroyo, P. Density functional theory study of the Lewis acidcatalyzed Diels-Alder reaction of nitroalkenes with vinyl ethers using aluminum derivatives. J. Phys. Org. Chem. 2002, 15, 660-666.
125. Domingo, L.R.; Aurell, M.J.; Pérez, P.; Contreras, R. Quantitative characterization of the global electrophilicity power of common diene/dienophile pairs in Diels-Alder reactions. Tetrahedron 2002, 58, 4417-4423.
126. Pérez, P.; Toro-Labbé, A.; Contreras, R. Solvent effects on electrophilicity. J. Am. Chem. Soc. 2001, 123, 5527-5531.
127. Meneses, L.; Fuentealba, P.; Contreras, R. On the variations of electronic chemical potential and chemical hardness induced by solvent effects. Chem. Phys. Lett. 2006, 433, 54-57.
128. Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. Effect of electric field on the global and local reactivity indices. Chem. Phys. Lett. 2003, 382, 48-56.
129. Parthasarathi, R.; Padmanabhan, J.; Subramanian, V.; Maiti, B.; Chattaraj, P.K. Chemical reactivity profiles of two selected polychlorinated biphenyls. J. Phys. Chem. A 2003, 107, 10346-10352.
130. Parthasarathi, R.; Subramanian, V.; Roy, D.R.; Chattaraj, P.K. Electrophilicity index as a possible descriptor of biological activity. Bioorg. Med. Chem. 2004, 12, 5533-5543.
131. Padmanabhan, J.; Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. Molecular structure, reactivity, and toxicity of the complete series of chlorinated benzenes. J. Phys. Chem. A. 2005, 109, 11043-11049.
132. Padmanabhan, J.; Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. Chemical reactivity indices for the complete series of chlorinated benzenes: solvent effect. J. Phys. Chem. A 2006, 110, 2739-2745.
133. Padmanabhan, J.; Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. Group philicity and electrophilicity as possible descriptors for modeling ecotoxicity applied to chlorophenols. Chem. Res. Toxicol. 2006, 19, 356-364.
134. Rong, C.; Lian, S.; Yin, D.; Zhong, A.; Zhang, R.; Liu, S. Effective simulation of biological systems: choice of density functional and basis set for heme-containing complexes. Chem. Phys. Lett. 2007, 434, 149-154.
135. Roy, D.R.; Pal, N.; Mitra, A.; Bultinck, P.; Parthasarathi, R.; Subramanian, V.; Chattaraj, P.K. An atom counting strategy towards analyzing the biological activity of sex hormones. Eur. J. Med. Chem. 2007, 42, 1365-1369.
136. Schultz, T.W.; Hewitt, M.; Netzeva, T.I.; Cronin M.T.D. Assessing applicability domains of toxicological QSARs: Definition, Confidence in predicted values, And the role of mechanisms of action. QSAR Comb. Sci. 2007, 26, 238-254.
137. Netzeva, T.I.; Gallegos, A.; Worth, A.P. Comparison of the applicability domain of a QSAR for estrogenicity with a large chemical inventory. Environ. Toxicol. Chem. 2006, 25, 1223-1230.
138. Roberts, D.W.; Aptula, A.O.; Patlewicz, G. Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the Schiff base applicability domain for skin sensitization. Chem. Res. Toxicol. 2006, 19, 1228-1233.
139. Aptula, A.O.; Patlewicz, G.; Roberts, D.W. Skin sensitization: Reaction mechanistic applicability domains for Structure-Activity Relationships. Chem. Res. Toxicol. 2005, 18, 1420-1426.
140. Program Package, HyperChem 7.01; Hypercube, Inc.: Gainesville, FL, USA, 2002.
141. Putz, M.V. On absolute aromaticity within electronegativity and chemical hardness reactivity pictures. MATCH Commun. Math. Comput. Chem. 2010, 64, 391-418.
142. Lele, S.K. Compact finite difference schemes with spectral-like resolution. J. Comput. Phys. 1992, 103, 16-42.
143. ViiV Healthcare Group of Companies. The biology of HIV, 2012. Available online: http://www.apositivelife.com/forasos/biology-of-hiv.html (accessed on 4 May 2013))
144. Genetic Engineering & Biotechnology News. Pfizer Inks Deal with K.U. Leuven for HIV drugs with new mechanism of action. 2010. Available online: http://www.genengnews.com/gen-newshighlights/pfizer-inks-deal-with-k-u-leuven- for-hiv-drugs-with-new-mechanism-of-action/81243931/ (accessed on 5 April 2013).
145. Aksimentiev, A.; Heng, J.B.; Timp, G.; Schulten K. Microscopic kinetics of DNA translocation through synthetic nanopores. Biophys. J. 2004, 87, 2086-2097.
146. Heng, J.B.; Ho, C.; Kim, T.; Timp, R.; Aksimentiev, A.; Grinkova, Y.V.; Sligar, S.; Schulten, K.; Timp, G. Sizing DNA using a nanometer-diameter pore. Biophys. J. 2004, 87, 2905-2911.
147. Perilla, J.R.; Zhao, G.; Chandler, D.; Gronenborn, A.; Zhang, P.; Schulten, K. Refinement of Atomic Models of HIV-1 Oligomers. Available online: http://www.ks.uiuc.edu/ (accessed on 5 April 2013).
148. Ganser-Pornillos, B.K.; Yeager, M.; Sundquist, W.I. The structural biology of HIV assembly. Curr. Opin. Struct. Biol. 2008, 18, 203-217.
149. Picado, M.J. Avances en la diseminación del VIH, La Ciencia y sus Demonios, 30 April 2012. Available online: http://lacienciaysusdemonios.com/ 2012/04/30/avances-en-la-diseminacion-delvih/#more-24038 (accessed on 5 April 2013).
150. C.H.A.N.G.E. - Counteracting HIV/AIDS through new gene enhancement. Available online: http://dev.nsta.org/evwebs/577/Present-Technology-Page.html (accessed on 5 April 2013).
151. Madrid, M.; Jacobo-Molina, A.; Ding, J.; Arnold, E. Major subdomain rearrangement in HIV-1 reverse transcriptase simulated by molecular dynamics. Proteins Struct. Funct. Bioinf. 1999, 35, 332-337.
152. Topliss, J.G.; Costello, J.D. Chance correlation in structure-activity studies using multiple regression analysis. J. Med. Chem. 1972, 15, 1066-1069.
153. Puzyn, T.; Mostrag-Szlichtyng, A.; Gajewicz, A.; Skrzynski, M.; Worth, A.P. Investigating the influence of data splitting on the predictive ability of QSAR/QSPR models. Struct. Chem. 2011, 22, 795-804.
154. Pavan, M.; Netzeva, T.I.; Worth, A.P. Validation of a QSAR Model for Acute Toxicity. SAR QSAR Environ. Res. 2006, 17, 147-171.
155. Putz, M.V.; Lazea, M.; Putz, A.M.; Seiman-Duda, C. Introducing Catastrophe-QSAR. Application on Modeling Molecular Mechanisms of Pyridinone Derivative-Type HIV Non-Nucleoside Reverse Transcriptase Inhibitors. Int. J. Mol. Sci. 2011, 12, 9533-9569..
156. Balaban, A.T. Chemical Applications of Graph Theory; Academic Press: London, UK, 1976.
157. Balaban, A.T. Highly discriminating distance-based topological index. Chem. Phys. Lett. 1982, 89, 399-404.
158. Basak, S.C.; Mills, D.R.; Balaban, A.T.; Gute, B.D. Prediction of mutagenicity of aromatic and heteroaromatic amines from structure: a hierarchical QSAR approach. J. Chem. Inf. Comput. Sci. 2011, 41, 671-678.
159. Balaban, A.T. From chemical topology to 3D geometry. J. Chem. Inf. Comput. Sci. 1997, 37, 645-650.
160. Lewis, G.N. The atom and the molecule. J. Am. Chem. Soc. 1916, 38, 762-785.
161. Pauling, L.; Wheland, G.W. The nature of the chemical bond. V. The quantum-mechanical calculation of the resonance energy of benzene and naphthalene and the hydrocarbon free radicals. J. Chem. Phys. 1933, 1, 362-375.
162. Pauling, L.; Sherman, J. The nature of the chemical bond. VI. The calculation from thermochemical data of the energy of resonance of molecules among several electronic structures. J. Chem. Phys. 1933, 1, 606-618.
163. Pauling, L.; Wilson, E.B. Introduction to Quantum Mechanics with Applications to Chemistry; McGraw-Hill: New York, NY, USA, 1935.
164. Wheland, G.W. The Theory of Resonance and its Application to Organic Chemistry; Wiley: New York, NY, USA, 1944.
165. Heitler, W.; London, F. Wechselwirkung neutraler Atome und homöopolare Bindung nach der Quantenmechanik. Z. Phys. 1927, 44, 455-472.
166. Hückel, E. Quantentheoretische Beiträge zum Benzolproblem. I. Z. Physik 1931, 71, 204-286.
167. Hückel, E. Quantentheoretische Beiträge zum Benzolproblem. II. Z. Physik 1931, 72, 310-337.
168. Hoffmann, R. An extended Hückel theory. I. Hydrocarbons. J. Chem. Phys. 1963, 39, 1397-1412.
169. Bader, R.F.W. Atoms in Molecules - A Quantum Theory; Oxford University Press: Oxford, UK, 1990.
170. Bader, R.F.W. Principle of stationary action and the definition of a proper open system. Phys. Rev. B 1994, 49, 13348-13356.
171. Bader, R.F.W. A bond path: a universal indicator of bonded interactions. J. Phys. Chem. A 1998, 102, 7314-7323.
172. Gillespie, R.J.; Nyholm, R.S. Inorganic stereochemistry. Quart. Rev. Chem. Soc. 1957, 11, 339-380.
173. Gillespie, R.J., Hargittai, I. The VSEPR Model of Molecular Geometry; Allyn and Bacon: Boston, MA, USA, 1991.
174. Kohn, W.; Becke, A.D.; Parr, R.G. Density functional theory of electronic structure. J. Phys. Chem. 1996, 100, 12974-12980.
175. Putz, M.V. Chemical action and chemical bonding. J. Mol. Structure THEOCHEM 2009, 900, 64-70.
176. Putz, M.V. Quantum parabolic effects of electronegativity and chemical hardness on carbon π-systems, In Carbon Bonding And Structures: Advances in Physics and Chemistry; Putz, M.V., Ed.; Springer Verlag: London, UK, 2011; pp. 1-32.
177. Putz, M.V. Quantum Theory: Density, Condensation, and Bonding; Apple Academics: Ontario, New Jersey, NJ, USA, 2012.