European Journal of Chemistry 2023, 14(3), 370-375 | doi: https://doi.org/10.5155/eurjchem.14.3.370-375.2455 | Get rights and content

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A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development


Mohammad Suhail (1,*) orcid , Safwana Usmani (2) orcid , Mehmood Ahmad (3) orcid

(1) Department of Chemistry, Siddhartha (P.G.) College, Aakhlaur Kheri (Saharanpur), Uttar Pradesh-247554, India
(2) Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi-110025, India
(3) Department of Chemistry, Bhaila (P.G.) College, Deoband (Saharanpur), Uttar Pradesh-247554, India
(*) Corresponding Author

Received: 27 May 2023 | Revised: 17 Jul 2023 | Accepted: 26 Jul 2023 | Published: 30 Sep 2023 | Issue Date: September 2023

Abstract


Sickle cell anemia disease has been a great challenge for the world in the present situation. It occurs only due to the polymerization of sickle hemoglobin (HbS) having Pro-Val-Glu (PVG) typed mutation, while the polymerization does not occur in normal hemoglobin (HbA) having Pro-Glu-Glu (PGG) residues. According to data from the literature, Val-beta6 of Pro-Val-Glu is hydrophobic in nature, which appears to fit into a hydrophobic pocket in the adjacent HbS. After the insertion of Pro-Val-Glu into a hydrophobic pocket on the adjacent HbS, the polymerization is started. This is a questionable point on how the replacement of glutamic acid with valine in HbS makes it more reactive to fit into a hydrophobic pocket on adjacent HbS for polymerization. No data from the literature on the reactivity of HbS for polymerization was found yet. This is the first time that the theoretical calculation was done in both HbA and HbS where they were structurally different. After that, a comparative study between PVG and PGG was done at quantum level for the evaluation of the reactivity to fit into a hydrophobic pocket on adjacent HbS. At a quantum level, it was found that the HOMO-LUMO gap of Pro-Val-Glu was lower than that of Pro-Glu-Glu. According to the data from the literature, the lesser HOMO-LUMO gap promotes the initiation of the polymerization reaction. On the basis of the results, it was also shown how the mutation point (Pro-Val-Glu) in HbS becomes more reactive to polymerization, whereas Pro-Glu-Glu in HbA does not. The computational method developed for the first time will be very helpful not only for molecular biologists but also for computational and medicinal chemists. Additionally, the required modifications based on gaps in anti-sickling drug development are also suggested in the presented article.


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European Journal of Chemistry

Keywords


Mutation; Polymerization; Sickle cell anemia; HOMO-LUMO gap; Theoretical calculation; Drug development and gaps

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DOI: 10.5155/eurjchem.14.3.370-375.2455

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References


[1]. Pauling, L.; Itano, H. A.; Singer, S. J.; Wells, I. C. Sickle cell anemia, a molecular disease. Science 1949, 110, 543-548.
https://doi.org/10.1126/science.110.2865.543

[2]. Ingram, V. M. Gene mutations in human hæmoglobin: The chemical difference between normal and sickle cell hæmoglobin. Nature 1957, 180, 326-328.
https://doi.org/10.1038/180326a0

[3]. May, A.; Huehns, E. R. The mechanism of the low oxygen affinity of red cells in sickle cell disease. Hamatol. Bluttransfus. 1972, 10, 279-283.
https://doi.org/10.1042/cs042010Pa

[4]. Becklake, M. R.; Griffiths, S. B.; McGregor, M.; Goldman, H. I.; Schreve, J. P. Oxygen dissociation curves in sickle cell anemia and in subjects with the sickle cell trait. J. Clin. Invest. 1955, 34, 751-755.
https://doi.org/10.1172/JCI103129

[5]. Fabry, M. E.; Desrosiers, L.; Suzuka, S. M. Direct intracellular measurement of deoxygenated hemoglobin S solubility. Blood 2001, 98, 883-884.
https://doi.org/10.1182/blood.V98.3.883

[6]. Gill, S. J.; Sköld, R.; Fall, L.; Shaeffer, T.; Spokane, P.; Wyman, J. Aggregation effects on oxygen binding of sickle cell hemoglobin. Science 1978, 201, 362-364.
https://doi.org/10.1126/science.663663

[7]. Adachi, K.; Konitzer, P.; Paulraj, C. G.; Surrey, S. Role of Leu-beta 88 in the hydrophobic acceptor pocket for Val-beta 6 during hemoglobin S polymerization. J. Biol. Chem. 1994, 269, 17477-17480.
https://doi.org/10.1016/S0021-9258(17)32465-1

[8]. Ferrone, F. A.; Ivanova, M.; Jasuja, R. Heterogeneous nucleation and crowding in sickle hemoglobin: An analytic approach. Biophys. J. 2002, 82, 399-406.
https://doi.org/10.1016/S0006-3495(02)75404-0

[9]. Dash, B.; Archana, Y.; Satapathy, N.; Naik, S. Search for antisickling agents from plants. Pharmacogn. Rev. 2013, 7, 53.
https://doi.org/10.4103/0973-7847.112849

[10]. Marengo-Rowe, A. J. Structure-function relations of human hemoglobins. Proc. (Bayl. Univ. Med. Cent.) 2006, 19, 239-245.
https://doi.org/10.1080/08998280.2006.11928171

[11]. Rotter, M. A.; Kwong, S.; Briehl, R. W.; Ferrone, F. A. Heterogeneous nucleation in sickle hemoglobin: Experimental validation of a structural mechanism. Biophys. J. 2005, 89, 2677-2684.
https://doi.org/10.1529/biophysj.105.067785

[12]. Martin, D. W.; Mayes, P. A.; Rodwell, V. W. Harper's review of biochemistry; Lange Medical Publications: California, 1981.

[13]. Abdulmalik, O.; Pagare, P. P.; Huang, B.; Xu, G. G.; Ghatge, M. S.; Xu, X.; Chen, Q.; Anabaraonye, N.; Musayev, F. N.; Omar, A. M.; Venitz, J.; Zhang, Y.; Safo, M. K. VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Sci. Rep. 2020, 10, 20277.
https://doi.org/10.1038/s41598-020-77171-2

[14]. Zaugg, R. H.; Walder, J. A.; Klotz, I. M. Schiff base adducts of hemoglobin. Modifications that inhibit erythrocyte sickling. J. Biol. Chem. 1977, 252, 8542-8548.
https://doi.org/10.1016/S0021-9258(19)75254-5

[15]. Oder, E.; Safo, M. K.; Abdulmalik, O.; Kato, G. J. New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br. J. Haematol. 2016, 175, 24-30.
https://doi.org/10.1111/bjh.14264

[16]. Hutchaleelaha, A.; Patel, M.; Silva, A.; Oksenberg, D.; Metcalf, B. GBT440 demonstrates high specificity for red blood cells in nonclinical species. Blood 2015, 126, 2172-2172.
https://doi.org/10.1182/blood.V126.23.2172.2172

[17]. Pagare, P. P.; Ghatge, M. S.; Musayev, F. N.; Deshpande, T. M.; Chen, Q.; Braxton, C.; Kim, S.; Venitz, J.; Zhang, Y.; Abdulmalik, O.; Safo, M. K. Rational design of pyridyl derivatives of vanillin for the treatment of sickle cell disease. Bioorg. Med. Chem. 2018, 26, 2530-2538.
https://doi.org/10.1016/j.bmc.2018.04.015

[18]. Metcalf, B.; Chuang, C.; Dufu, K.; Patel, M. P.; Silva-Garcia, A.; Johnson, C.; Lu, Q.; Partridge, J. R.; Patskovska, L.; Patskovsky, Y.; Almo, S. C.; Jacobson, M. P.; Hua, L.; Xu, Q.; Gwaltney, S. L., II; Yee, C.; Harris, J.; Morgan, B. P.; James, J.; Xu, D.; Hutchaleelaha, A.; Paulvannan, K.; Oksenberg, D.; Li, Z. Discovery of GBT440, an orally bioavailable R-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 2017, 8, 321-326.
https://doi.org/10.1021/acsmedchemlett.6b00491

[19]. Stern, W.; Mathews, D.; McKew, J.; Shen, X.; Kato, G. J. A phase 1, first-in-man, dose-response study of AEs-103 (5-HMF), an anti-sickling, allosteric modifier of hemoglobin oxygen affinity in healthy Norman volunteers. Blood 2012, 120, 3210-3210.
https://doi.org/10.1182/blood.V120.21.3210.3210

[20]. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Gaussian Inc., Wallingford CT, 2004.

[21]. Dennington, R.; Keith, T. A.; Millam, J. M. GaussView, Version 6, Semichem Inc.; Shawnee Mission, KS, 2016.

[22]. Dassault Systѐmes BIOVIA, BIOVIA Workbook, Release 2017; BIOVIA DS Visualizer, Release 2021, San Diego: Dassault Systѐmes, 2021. https://discover.3ds.com/discovery-studio-visualizer-download (accessed 2022-05-10).

[23]. Cousins, K. R. Computer review of ChemDraw ultra 12.0. J. Am. Chem. Soc. 2011, 133, 8388-8388.
https://doi.org/10.1021/ja204075s

[24]. Suhail, M.; Mukhtar, S. D.; Ali, I.; Ansari, A.; Arora, S. Theoretical DFT study of Cannizzaro reaction mechanism: A mini perspective. Eur. J. Chem. 2020, 11, 139-144.
https://doi.org/10.5155/eurjchem.11.2.139-144.1975

[25]. Ali, I.; Suhail, M.; Asnin, L. Chiral separation and modeling of quinolones on teicoplanin macrocyclic glycopeptide antibiotics CSP. Chirality 2018, 30, 1304-1311.
https://doi.org/10.1002/chir.23024

[26]. Ali, I.; Suhail, M.; ALOthman, Z. A.; Al-Mohaimeed, A. M.; Alwarthan, A. Chiral resolution of four stereomers and simulation studies of newly synthesized antibacterial agents having two chiral centers. Sep. Purif. Technol. 2020, 236, 116256.
https://doi.org/10.1016/j.seppur.2019.116256

[27]. ALOthman, Z. A.; ALanazi, A. G.; Suhail, M.; Ali, I. HPLC enantio-separation and chiral recognition mechanism of quinolones on vancomycin CSP. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2020, 1157, 122335.
https://doi.org/10.1016/j.jchromb.2020.122335

[28]. ALOthman, Z. A.; Badjah, A. Y.; Alsheetan, K. M.; Suhail, M.; Ali, I. Enantiomeric resolution of quinolones on crown ether CSP: Thermodynamics, chiral discrimination mechanism and application in biological samples. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2021, 1166, 122550.
https://doi.org/10.1016/j.jchromb.2021.122550

[29]. Suhail, M. In vitro anticancer, antioxidant and DNA-binding study of the bioactive ingredient of clove and its isolation. Eur. J. Chem. 2022, 13, 33-40.
https://doi.org/10.5155/eurjchem.13.1.33-40.2158

[30]. Suhail, M.; Ali, I. An advanced computational evaluation for the most biologically active enantiomers of chiral anti-cancer agents. Anticancer Agents Med. Chem. 2021, 21, 2075-2081.
https://doi.org/10.2174/1871520621999201230233811

[31]. Suhail, M. A computational and literature-based evaluation for a combination of chiral anti-CoV drugs to block and eliminate SARS-CoV-2 safely. J. Comput. Biophys. Chem. 2021, 20, 417-432.
https://doi.org/10.1142/S2737416521500228

[32]. Suhail, M. The target determination and the mechanism of action of chiral-antimalarial drugs: A docking approach. J. Comput. Biophys. Chem. 2021, 20, 501-516.
https://doi.org/10.1142/S2737416521500290

[33]. Suhail, M. The mystery of chemistry behind the mechanism of action of anti-HIV drugs: A docking approach at an atomic level. Eur. J. Chem. 2021, 12, 432-438.
https://doi.org/10.5155/eurjchem.12.4.432-438.2149

[34]. Rengasamy, V.; Suhail, M.; Jain, A. Green synthesis of uracil derivatives, DNA binding study and docking-based evaluation of their anti-cancer and anti-viral potencies. Act Scie Pharma 2022, 116-133.
https://doi.org/10.31080/ASPS.2022.06.0842

[35]. Harrington, D. J.; Adachi, K.; Royer, W. E., Jr The high resolution crystal structure of deoxyhemoglobin S. J. Mol. Biol. 1997, 272, 398-407.
https://doi.org/10.1006/jmbi.1997.1253

[36]. Dapprich, S.; Komáromi, I.; Byun, K. S.; Morokuma, K.; Frisch, M. J. A new ONIOM implementation in Gaussian98. Part I. The calculation of energies, gradients, vibrational frequencies and electric field derivatives. Theochem 1999, 461-462, 1-21.
https://doi.org/10.1016/S0166-1280(98)00475-8

[37]. Čársky, P.; Hubač, I. Restricted Hartree-Fock and unrestricted Hartree-Fock as reference states in many-body perturbation theory: a critical comparison of the two approaches. Theoret. Chim. Acta 1991, 80, 407-425.
https://doi.org/10.1007/BF01117420

[38]. Becke, A. D. Density‐functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652.
https://doi.org/10.1063/1.464913

[39]. Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. V. R. Efficient diffuse function-augmented basis sets for anion calculations. III. The 3-21+G basis set for first-row elements, Li-F. J. Comput. Chem. 1983, 4, 294-301.
https://doi.org/10.1002/jcc.540040303

[40]. Berger, T. A.; Berger, B. K.; Kogelman, K. Supercritical Fluid Chromatography for Chiral Analysis and Semi-preparative Purification. In Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; Elsevier, 2022.
https://doi.org/10.1016/B978-0-32-390644-9.00013-5

[41]. Berinde, Z. M. QSPR models for the molar refraction, polarizability and refractive index of aliphatic carboxylic acids using the ZEP topological index. Symmetry (Basel) 2021, 13, 2359.
https://doi.org/10.3390/sym13122359

[42]. Huang, G.; Lu, C.-H.; Yang, H.-H. Magnetic Nanomaterials for Magnetic Bioanalysis. In Novel Nanomaterials for Biomedical, Environmental and Energy Applications; Elsevier, 2019; pp. 89-109.
https://doi.org/10.1016/B978-0-12-814497-8.00003-5

[43]. Vistoli, G.; Pedretti, A. Molecular fields to assess recognition forces and property spaces. In Comprehensive Medicinal Chemistry II; Elsevier, 2007; pp. 577-602.
https://doi.org/10.1016/B0-08-045044-X/00142-5

[44]. Aihara, J.-I. Reduced HOMO−LUMO gap as an index of kinetic stability for polycyclic aromatic hydrocarbons. J. Phys. Chem. A 1999, 103, 7487-7495.
https://doi.org/10.1021/jp990092i

[45]. Manolopoulos, D. E.; May, J. C.; Down, S. E. Theoretical studies of the fullerenes: C34 to C70. Chem. Phys. Lett. 1991, 181, 105-111.
https://doi.org/10.1016/0009-2614(91)90340-F

[46]. Ruiz-Morales, Y. HOMO−LUMO gap as an index of molecular size and structure for polycyclic aromatic hydrocarbons (PAHs) and asphaltenes: A theoretical study. I. J. Phys. Chem. A 2002, 106, 11283-11308.
https://doi.org/10.1021/jp021152e

[47]. Mumit, M. A.; Pal, T. K.; Alam, M. A.; Islam, M. A.-A.-A.-A.; Paul, S.; Sheikh, M. C. DFT studies on vibrational and electronic spectra, HOMO-LUMO, MEP, HOMA, NBO and molecular docking analysis of benzyl-3-N-(2,4,5-trimethoxyphenylmethylene)hydrazinecarbodithioate. J. Mol. Struct. 2020, 1220, 128715.
https://doi.org/10.1016/j.molstruc.2020.128715

[48]. Suhail, M. A theoretical density functional theory calculation-based analysis of conformers of p-xylene. Eur. J. Chem. 2022, 13, 224-229.
https://doi.org/10.5155/eurjchem.13.2.224-229.2237

[49]. Zhong, H.; Er, D.; Dong, L.; Wen, L. Theoretical study on the poly(m-phenylene) derivatives with lower HOMO-LUMO gaps. Synth. Met. 2017, 229, 16-21.
https://doi.org/10.1016/j.synthmet.2017.04.016

[50]. Volkenstein, M. V. Coding of polar and non-polar amino-acids. Nature 1965, 207, 294-295.
https://doi.org/10.1038/207294a0

[51]. Gopalsamy, A.; Aulabaugh, A. E.; Barakat, A.; Beaumont, K. C.; Cabral, S.; Canterbury, D. P.; Casimiro-Garcia, A.; Chang, J. S.; Chen, M. Z.; Choi, C.; Dow, R. L.; Fadeyi, O. O.; Feng, X.; France, S. P.; Howard, R. M.; Janz, J. M.; Jasti, J.; Jasuja, R.; Jones, L. H.; King-Ahmad, A.; Knee, K. M.; Kohrt, J. T.; Limberakis, C.; Liras, S.; Martinez, C. A.; McClure, K. F.; Narayanan, A.; Narula, J.; Novak, J. J.; O'Connell, T. N.; Parikh, M. D.; Piotrowski, D. W.; Plotnikova, O.; Robinson, R. P.; Sahasrabudhe, P. V.; Sharma, R.; Thuma, B. A.; Vasa, D.; Wei, L.; Wenzel, A. Z.; Withka, J. M.; Xiao, J.; Yayla, H. G. PF-07059013: A noncovalent modulator of hemoglobin for treatment of sickle cell disease. J. Med. Chem. 2021, 64, 326-342.
https://doi.org/10.1021/acs.jmedchem.0c01518

[52]. Moioli, E.; Schmid, L.; Wasserscheid, P.; Freund, H. pH effects in the acetaldehyde-ammonia reaction. React. Chem. Eng. 2017, 2, 382-389.
https://doi.org/10.1039/C7RE00006E


How to cite


Suhail, M.; Usmani, S.; Ahmad, M. Eur. J. Chem. 2023, 14(3), 370-375. doi:10.5155/eurjchem.14.3.370-375.2455
Suhail, M.; Usmani, S.; Ahmad, M. A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development. Eur. J. Chem. 2023, 14(3), 370-375. doi:10.5155/eurjchem.14.3.370-375.2455
Suhail, M., Usmani, S., & Ahmad, M. (2023). A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development. European Journal of Chemistry, 14(3), 370-375. doi:10.5155/eurjchem.14.3.370-375.2455
Suhail, Mohammad, Safwana Usmani, & Mehmood Ahmad. "A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development." European Journal of Chemistry [Online], 14.3 (2023): 370-375. Web. 10 Dec. 2023
Suhail, Mohammad, Usmani, Safwana, AND Ahmad, Mehmood. "A quantum chemistry background of sickle cell anemia and gaps in antisickling drug development" European Journal of Chemistry [Online], Volume 14 Number 3 (30 September 2023)

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