The closo-1,2-C2B10H12 carborane is a recognized 3D aromatic icosahedral building block, with an electron distribution governed by the outer hydridic BH and acidic CH vertices. We attached the carborane cage to a peptidomimetic scaffold to generate an active-site inhibitor of SmCB1, a protease drug target in the Schistosoma pathogen. The carborane-tagged compound exhibited superior inhibitor affinity and bioactivity compared to its conventional 2D aromatic phenyl analog. Quantum mechanical computations, based on the crystal structure of the protease-inhibitor complex, revealed that the carborane tag contributed to inhibitor binding not only through nonpolar interactions but also via a key hydrogen bond between its CH vertex and a negatively charged residue in the binding site. This interaction, driven by the large dipole moment of the carborane cage, resulted in a more favorable energy contribution than that of the phenyl group in the 2D analog. The carborane pharmacophore boosted affinity for SmCB1 and conferred specific anti-schistosomal activity, highlighting its potential in protein ligand design.

Center for Discovery and Innovation in Parasitic Diseases Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego 9255 Pharmacy Lane MC0657 La Jolla CA 92093 USA

Institute of Inorganic Chemistry of the Czech Academy of Sciences Husinec Řež 250 68 Czech Republic

Institute of Medicinal Microbiology 1st Faculty of Medicine Charles University and General University Hospital Prague Studničkova 7 12800 Prague 2 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague 6 Czech Republic

Medicinal and Biological Chemistry Group São Carlos Institute of Chemistry University of São Paulo Avenue Trabalhador Sancarlense 400 13566 590 São Carlos SP Brazil

Pharmaceutical Institute Pharmaceutical and Medicinal Chemistry University of Bonn An der Immenburg 4 53121 Bonn Germany

Zobrazit více v PubMed

Grams R. J. Santos W. L. Scorei I. R. Abad-García A. Rosenblum C. A. Bita A. Cerecetto H. Viñas C. Soriano-Ursúa M. A. The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology. Chem. Rev. 2024;124(5):2441–2511. PubMed

Leśnikowski Z. J. Challenges and Opportunities for the Application of Boron Cluster in Drug Design. J. Med. Chem. 2016;59(17):7738–7758. PubMed

Boron Science: New Technologies and Applications, ed. N. S. Hosmane, CRC Press, 2012

Handbook of Boron Science: With Applications in Organometallics, Catalysis, Materials and Medicine, ed. H. R. Eagling, World Scientific, 2018

Boron-Based Compounds: Potential and Emerging Applications in Medicine, ed. C. Vińas and E. Hey-Hawkins, Wiley, 2018

Hosmane N. S., Maguire J. A., Zhu Y. and Takagi M., Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment, World Scientific, 2012

Poater J. Solà M. Viñas C. Teixidor F. π Aromaticity and Three-Dimensional Aromaticity: Two sides of the Same Coin? Angew. Chem., Int. Ed. 2014;53(45):12191–12195. PubMed

Poater J. Viñas C. Bennour I. Escayola S. Solà M. Teixidor F. Too Persistent to Give Up: Aromaticity in Boron Clusters Survives Radical Structural Changes. J. Am. Chem. Soc. 2020;142(20):9396–9407. PubMed

Grimes R. N., Carboranes, Elsevier, Amsterdam, The Netherlands, 3rd edn, 2016

Fanfrlík J. Lepšík M. Horinek D. Havlas Z. Hobza P. Interaction of Carboranes with Biomolecules: Formation of Dihydrogen Bonds. ChemPhysChem. 2006;7(5):1100–1105. PubMed

Pecina A. Lepšík M. Řezáč J. Brynda J. Mader P. Řezáčová P. Hobza P. Fanfrlík J. QM/MM Calculations Reveal the Different Nature of the Interaction of two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II. J. Phys. Chem. B. 2013;117(50):16096–16104. PubMed

Fanfrlík J. Pecina A. Řezáč J. Sedlak R. Hnyk D. Lepšík M. Hobza P. B–H⋯π: A Nonclassical Hydrogen Bond or Dispersion Contact? Phys. Chem. Chem. Phys. 2017;19(28):18194–18200. PubMed

Hnyk D. Všetečka V. Drož L. Exner O. Charge Distribution within 1,2-dicarba-closododecaborane: Dipole Moments of its Phenyl Derivatives. Collect. Czech. Chem. Commun. 2001;66:1375–1379.

Endo Y. Iijima T. Yamakoshi Y. Fukasawa H. Miyaura C. Inada M. Kubo A. Itai A. Potent Estrogen Agonists Based on Carborane as a Hydrophobic Skeletal Structure: A New Medicinal Application of Boron Clusters. Chem. Biol. 2001;8(4):341–355. PubMed

Yamamoto K. Endo Y. Utility of Boron Clusters for Drug Design. Hansch–Fujita Hydrophobic Parameters π of Dicarba-closo-Dodecaboranyl Groups. Bioorg. Med. Chem. Lett. 2001;11(17):2389–2392. PubMed

Chen Y. Du F. Tang L. Xu J. Zhao Y. Wu X. Li M. Shen J. Wen Q. Cho Ch. H. Xiao Z. Carboranes as Unique Pharmacophores in Antitumor Medicinal Chemistry. Mol. Ther.: Oncol. 2022;24:400–416. PubMed PMC

Worm D. J. Hoppenz S. Els-Heindl S. Kellert M. Kuhnert R. Saretz S. Köbberling J. Riedl B. Hey-Hawkins E. Beck-Sickinger A. G. Selective Neuropeptide Y Conjugates with Maximized Carborane Loading as Promising Boron Delivery Agents for Boron Neutron Capture Therapy. J. Med. Chem. 2020;63(5):2358–2371. PubMed

Quan Y. Xie Z. Controlled Functionalization of o-Carborane via, Transition Metal Catalyzed B-H Activation. Chem. Soc. Rev. 2019;48(13):3660–3673. PubMed

Caffrey C. R. McKerrow J. H. Salter J. P. Sajid M. Blood ‘n’ Guts: An Update on Schistosome Digestive Peptidases. Trends Parasitol. 2004;20(5):241–248. PubMed

Abdulla M. H. Lim K. C. Sajid M. McKerrow J. H. Caffrey C. R. Schistosomiasis mansoni: Novel Chemotherapy Using a Cysteine Protease Inhibitor. PLoS Med. 2007;4(1):e14. PubMed PMC

McManus D. P. Dunne D. W. Sacko M. Utzinger J. Vennerval B. J. Zhou X. N. Schistosomiasis. Nat. Rev. Dis. Primers. 2018;4:13. PubMed

Caffrey C. R. Chemotherapy of schistosomiasis: present and future. Curr. Opin. Chem. Biol. 2007;11(4):433–439. PubMed

WHO, Schistosomiasis. Status in endemic countries. https://apps.who.int/neglected_diseases/ntddata/sch/sch.html

Jílková A. Rubešová P. Fanfrlík J. Fajtová P. Řezáčová P. Brynda J. Lepšík M. Mertlíková-Kaiserová H. Emal C. D. Renslo A. R. Roush W. R. Horn M. Caffrey C. R. Mareš M. Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors. ACS Infect. Dis. 2021;7(5):1077–1088. PubMed PMC

Jílková A. Řezáčová P. Lepšík M. Horn M. Váchová J. Fanfrlík J. Brynda J. McKerrow J. H. Caffrey C. R. Mareš M. Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni. J. Biol. Chem. 2011;286(41):35770–35781. PubMed PMC

Jílková A. Horn M. Fanfrlík J. Küppers J. Pachl P. Řezáčová P. Lepšík M. Fajtová P. Rubešová P. Chanová M. Caffrey C. R. Gütschow M. Mareš M. Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity. ACS Infect. Dis. 2021;7(1):189–201. PubMed PMC

Vale N. Gouveia M. J. Rinaldi G. Brindley P. J. Gärtner F. Correia da Costa J. M. Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance. Antimicrob. Agents Chemother. 2017;61(5):e02582. PubMed PMC

Doenhoff M. J. Pica-Mattoccia L. Praziquantel for the Treatment of Schistosomiasis: Its Use for Control in Areas with Endemic Disease and Prospects for Drug Resistance. Expert Rev. Anti-Infect. Ther. 2006;4(2):199–210. PubMed

Caffrey C. R., El-Sakkary N., Mäder P., Krieg R., Becker K., Schlitzer M., Drewry D. H., Vennerstrom J. L. and Grevelding C. G., Drug Discovery and Development for Schistosomiasis in Neglected Tropical Diseases, ed. D. Swinney, M. Pollastri, R. Mannhold, H. Buschmann and J. Holenz, 2019, pp. 187–225

Frizler M. Stirnberg M. Sisay M. T. Gütschow M. Development of Nitrile-Based Peptidic Inhibitors of Cysteine Cathepsins. Curr. Top. Med. Chem. 2010;10:294–322. PubMed

Cianni L. Feldmann C. W. Gilberg E. Gütschow M. Juliano L. Leitão A. Bajorath J. Montanari C. A. Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity? J. Med. Chem. 2019;62(23):10497–10525. PubMed

Frizler M. Lohr F. Lülsdorff M. Gütschow M. Facing the gem-Dialkyl Effect in Enzyme Inhibitor Design: Preparation of Homocycloleucine-Based Azadipetide Nitriles. Chem. – Eur. J. 2011;17(41):11419–11423. PubMed

Breidenbach J. Lemke C. Pillaiyar T. Schäkel L. Al Hamwi G. Diett M. Gedschold R. Geiger N. Lopez V. Mirza S. Namasivayam V. Schiedel A. C. Sylvester K. Thimm D. Vielmuth C. Vu L. P. Zyulina M. Bodem J. Gütschow M. Müller C. E. Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors. Angew. Chem., Int. Ed. 2021;60(18):10423–10429. PubMed PMC

Löser R. Frizler M. Schilling K. Gütschow M. Azadipeptide Nitriles: Highly Potent and Proteolytically Stable Inhibitors of Papain-like Cysteine Proteases. Angew. Chem., Int. Ed. 2008;47(23):4331–4334. PubMed

Meusel M. Ambrozak A. Hecker T. K. Gütschow M. The Aminobarbituric Acid-Hydantoin Rearrangement. J. Org. Chem. 2003;68(12):4684–4693. PubMed

Löser R. Nieger M. Gütschow M. Synthesis and Crystal Structure of Benzyl [(1S,)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2-phenylethyl]carbamate. Crystals. 2012;2(3):1201–1209.

Stone J. A. McCrea J. B. Winter R. Zajic S. Stoch S. A. Clinical and Translational Pharmacology of the Cathepsin K Inhibitor Odanacatib Studied for Osteoporosis. Br. J. Clin. Pharmacol. 2019;85(6):1072–1083. PubMed PMC

Owen D. R. Allerton C. M. N. Anderson A. S. Aschenbrenner L. Avery M. Berritt S. Boras B. Cardin R. D. Carlo A. Coffman K. J. Dantonio A. Di L. Eng H. Ferre R. Gajiwala K. S. Gibson S. A. Greasley S. E. Hurst B. L. Kadar E. P. Kalgutkar A. S. Lee J. C. Lee J. Liu W. Mason S. W. Noell S. Novak J. J. Obach R. S. Ogilvie K. Patel N. C. Pettersson M. Rai D. K. Reese M. R. Sammons M. F. Sathish J. G. Singh R. S. P. Steppan C. M. Stewart A. E. Tuttle J. B. Updyke L. Verhoest P. R. Wei L. Yang Q. Zhu Y. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374(6575):1586–1593. PubMed

Giroud M. Kuhn B. Saint-Auret S. Kuratli C. Martin R. E. Schuler F. Diederich F. Kaiser M. Brun R. Schirmeister T. Haap W. 2H-,1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Tripanocidal Rhodesian Inhibitors by Structure-Based Design. J. Med. Chem. 2018;61(8):3370–3388. PubMed

Lemke C. Jílková A. Ferber D. Braune A. On A. Johe P. Zíková A. Schirmeister T. Mareš M. Horn M. Gütschow M. Two Tags in One Probe: Combining Fluorescence- and Biotin-based Detection of the Trypanosomal Cysteine Protease Rhodesain. Chem. – Eur. J. 2022;28(62):e202201636. PubMed PMC

Alves L. Santos D. A. Cendron R. Rocho F. R. Matos T. K. Leitão A. Montanari C. A. A Nitrile-Based Peptoids as Cysteine Protease Inhibitors. Bioorg. Med. Chem. 2021;41:116211–111621. PubMed

Plešek J. Janoušek Z. Heřmánek S. Direct Sulfhydrylation of Boranes and Heteroboranes, 1,2-Dicarba-closo-dodecaborane(12)-9-thiol, 9-HS-1,2,-C2B10H11. Inorg. Synth. 1983;22:241–243.

Jílková A. Horn M. Mareš M. Structural and Functional Characterization of Schistosoma mansoni, Cathepsin B1. Methods Mol. Biol. 2020;2151:145–158. PubMed

Cianni L. Lemke C. Gilberg E. Feldmann C. Rosini F. Rocho F. D. Ribeiro J. F. Tezuka D. Y. Lopes C. D. de Albuquerque S. Bajorath J. Laufer S. Leitão A. Gütschow M. Montanari C. A. Mapping the S1 and S1′ Subsites of Cysteine Proteases with new Dipeptidyl Nitrile Inhibitors as Trypanocidal Agents. PLoS Negl. Trop. Dis. 2020;14:e0007755. PubMed PMC

Mertens M. D. Schmitz J. Horn M. Furtmann N. Bajorath J. Mareš M. Gütschow M. A Coumarin-Labeled Vinyl Sulfone as Tripeptidomimetic Activity-Based Probe for Cysteine Cathepsins. ChemBioChem. 2014;15(7):955–959. PubMed

Lemke C. Benýšek J. Brajtenbach D. Breuer C. Jílková A. Horn M. Buša M. Ulrychová L. Illies A. Kubatzky K. F. Bartz U. Mareš M. Gütschow M. An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity. J. Med. Chem. 2021;64(18):13793–13806. PubMed

Štefanić S. Dvořák J. Horn M. Braschi S. Sojka D. Ruelas D. S. Suzuki B. Lim K. C. Hopkins S. D. McKerrow J. H. Caffrey C. R. RNA Interference in Schistosoma mansoni Schistosomula: Selectivity, Sensitivity and Operation for Larger-Scale Screening. PLoS Negl. Trop. Dis. 2010;4(10):e850. PubMed PMC

Fajtová P. Štefanič S. Hradilek M. Dvořák J. Vondrášek J. Jílková A. Ulrychová L. McKerrow J. H. Caffrey C. R. Mareš M. Horn M. Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. PLoS Negl. Trop. Dis. 2015;9(6):e0003827. PubMed PMC

Long T. Neitz R. J. Beasley R. Kalyanaraman C. Suzuki B. M. Jacobson M. P. Dissous C. McKerrow J. H. Drewry D. H. Zuercher W. J. Singh R. Caffrey C. R. Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. PLoS Negl. Trop. Dis. 2016;10(1):e0004356. PubMed PMC

Fuchs N. Zimmermann R. A. Schwickert M. Gunkel A. Zimmer C. Meta M. Schwickert K. Keiser J. Haeberli C. Kiefer W. Schirmeister T. Dual Strategy to Design New Agents Targeting Schistosoma mansoni: Advancing Phenotypic and SmCB1 Inhibitors for Improved Efficacy. ACS Infect. Dis. 2024;10(5):1664–1678. PubMed

Hardegger L. A. Kuhn B. Spinnler B. Anselm L. Ecabert R. Stihle M. Gsell B. Thoma R. Diez J. Benz J. Plancher J. M. Hartmann G. Isshiki Y. Morikami K. Shimma N. Haap W. Banner D. W. Diederich F. Halogen Bonding at the Activite Sites of Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments. ChemMedChem. 2011;6:2048–2054. PubMed

Dossetter A. G. Beeley H. Bowyer J. Cook C. R. Crawford J. J. Finlayson J. E. Heron N. M. Heyes C. Highton A. J. Hudson J. A. Jestel A. Kenny P. W. Krapp S. Martin S. MacFaul P. A. McGuire T. M. Gutierrez P. M. Morley A. D. Morris J. J. Page K. M. Ribeiro L. R. Sawney H. Steinbacher S. Smith C. Vickers M. (1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsine K, Inhibitor for the treatment of Osteoarthritis. J. Med. Chem. 2012;55(14):6363–6374. PubMed

Mantina M. Chamberlin A. C. Valero R. Cramer C. J. Truhlar D. G. Consistent van der Waals Radii for the Whole Main Group. J. Phys. Chem. A. 2009;113:5806–5812. PubMed PMC

Fanfrlík J. Bronowska A. K. Řezáč J. Přenosil O. Konvalinka J. Hobza P. A. Reliable Docking/Scoring Scheme Based on the Semiempirical Quantum Mechanical PM6-DH2 Method Accurately Covering Dispersion and H-Bonding: HIV-1 Protease with 22 Ligands. J. Phys. Chem. B. 2010;114:12666–12678. PubMed

Fanfrlík J. Brahmkshatriya P. S. Řezáč J. Jílková A. Horn M. Mareš M. Hobza P. Lepšík M. Quantum-Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of parasitic Schistosoma mansoni, Cysteine Peptidase by Vinyl Sulfone Inhibitors. J. Phys. Chem. B. 2013;117:14973–14982. PubMed

Jeziorski B. Moszynski R. Szalewicz K. Perturbation Theory Approach to Intermolecular Potential Energy Surfaces of van der Waals Complexes. Chem. Rev. 1994;94:1887–1930.

Abdulla M. H. Ruelas D. S. Wolff B. Snedecor J. Lim K. C. Xu F. Renslo A. R. Williams J. McKerrow J. H. Caffrey C. R. Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-throughput Phenotypic Screening. PLoS Negl. Trop. Dis. 2009;3(7):e478. PubMed PMC

Horn M. Jílková A. Vondrášek J. Marešová L. Caffrey C. R. Mareš M. Mapping the Propeptide of the Schistosoma mansoni Cathepsin B1 Drug Target: Modulation of Inhibition by Heparin and Design of Mimetic Inhibitors. ACS Chem. Biol. 2011;6(6):609–617. PubMed

Jílková A. Horn M. Řezáčová P. Marešová L. Fajtová P. Brynda J. Vondrášek J. McKerrow J. H. Caffrey C. R. Mareš M. Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch. Structure. 2014;22(12):1786–1798. PubMed

Basch P. F. Cultivation of Schistosoma mansoni in vitro. I. Establishment of Cultures from Cercariae and Development until Pairing. J. Parasitol. 1981;67(2):179–185. PubMed

Leontovyč A. Ulrychová L. Horn M. Dvořák J. Collection of Excretory/Secretory Products from Individual Developmental Stages of the Blood Fluke Schistosoma mansoni. Methods Mol. Biol. 2020;2151:55–63. PubMed

Dvořák J. Fajtová P. Ulrychová L. Leontovyč A. Rojo-Arreola L. Suzuki B. M. Horn M. Mareš M. Craik C. S. Caffrey C. R. O’Donoghue A. J. Excretion/Secretion Products from Schistosoma mansoni Adults, Eggs and Schistosomula Have Unique Peptidase Specificity Profiles. Biochimie. 2016;122:99–109. PubMed PMC

Glaser J. Schurigt U. Suzuki B. M. Caffrey C. R. Holzgrabe U. Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni. Molecules. 2015;20(6):10873–10883. PubMed PMC

Case D. A., Babin V., Berryman J. T., Betz R. M., Cai Q., Cerutti D. S., Cheatham III T. E., Darden T. A., Duke R. E., Gohlke H., Goetz A. W., Gusarov S., Homeyer N., Janowski P., Kaus J., Kolossváry I., Kovalenko A., Lee T. S., LeGrand S., Luchko T., Luo R., Madej B., Merz K. M., Paesani F., Roe D. R., Roitberg A., Sagui C., Salomon-Ferrer R., Seabra G., Simmerling C. L., Smith W., Swails J., Walker R. C., Wang J., Wolf R. M., Wu X. and Kollman P. A., AMBER 14, University of California, San Francisco, 2014

Maier J. A. Martinez C. Kasavajhala K. Wickstrom L. Hauser K. E. Simmerling C. Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J. Chem. Theory Comput. 2015;11:3696–3371. PubMed PMC

Fanfrlík J. Pecina A. Řezáč J. Lepšík M. Sárosi M. B. Hnyk D. Hobza P. Benchmark Data Sets of Boron Cluster Dihydrogen Bonding for the Validation of Approximate Computational Methods. ChemPhysChem. 2020;21:2599–2604. PubMed

Hostaš J. Řezáč J. Accurate DFT-D3 Calculations in a Small Basis Set. J. Chem. Theory Comput. 2017;13:3575–3585. PubMed

Řezáč J. Cuby: An Integrative Framework for Computational Chemistry. J. Comput. Chem. 2016;37:1230–1237. PubMed

Ahlrichs R. Bar M. Haser M. Horn H. Kölmel C. Electronic Structure Calculations on Workstation Computers: The Program System Turbomole. Chem. Phys. Lett. 1989;162:165–169.

Welch A. J. What Can We Learn from the Crystal Structures of Metallacarboranes? Crystals. 2017;7(8):234.

Turney J. M. Simmonett A. C. Parrish R. M. Hohenstein E. G. Evangelista F. Fermann J. T. Mintz B. J. Burns L. A. Wilke J. J. Abrams M. L. Russ N. J. Leininger M. L. Janssen C. L. Seidl E. T. Allen W. D. Schaefer H. F. King R. A. Valeev E. F. Sherrill C. D. Crawford T. D. PSI4: An Open-Source ab initio, Electronic Structure Program. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012;2:556–565.

Frisch J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Mennucci B., Petersson G. A., Nakatsuji H., Caricato M., Li X., Hratchian H. P., Izmaylov A. F., Bloino J., Zheng G., Sonnenberg J. L., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Montgomery Jr. J. A., Peralta J. E., Ogliaro F., Bearpark M., Heyd J. J., Brothers E., Kudin K. N., Staroverov V. N., Kobayashi R., Normand J., Raghavachari K., Rendell A., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Rega N., Millam J. M., Klene M., Knox J. E., Cross J. B., Bakken V., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O., Austin A. J., Cammi R., Pomelli C., Ochterski J. W., Martin R. L., Morokuma K., Zakrzewski V. G., Voth G. A., Salvador P., Dannenberg J. J., Dapprich S., Daniels A. D., Farkas Ö., Foresman J. B., Ortiz J. V., Cioslowski J. and Fox D. J., Gaussian 09, Gaussian Inc., Wallingford, CT, 2009

Flükiger P., Lüthi H. P., Portmann S. and Weber J., MOLEKEL 4.3, Swiss Center for Scientific Computing, Manno, Switzerland, 2000

Portmann S. and Lüthi H. P., Molekel: Chimia, 2007, vol. 28, pp. 555