The increasing cases of multidrug resistant tuberculosis (MDR-TB) or even extensively resistant drug-resistant TB (XDR-TB) worldwide shows a worrisome trend.1 Second-line drugs typically used for such cases were known to be less effective, had longer treatment periods and more significant side effects than the first-line drugs.2 Discovery of new antituberculosis drugs have also been dismal, as not many drugs are approved as antituberculosis agents in the past 50 years, thus, necessitating a new direction to tackle this problem.3 Instead of finding new drugs, using targeted drug delivery approach may be a viable approach to improve existing drug therapy.
Targeted drug delivery focused on increasing the amount of drug uptake at the target sites while decreasing the drug concentration at the non-target sites.4 Consequently, the drug is able to display its maximum effectiveness and exhibit fewer side effects due to lesser drug loss to non-target sites.5,6 Targeted drug delivery is categorised into two main types: passive and active drug targeting. Passive targeting involves taking advantage of the changed environment of the targeted cells such as loosen blood vasculature and cell junction caused by the disease itself,7 active targeting involves conjugating a targeting moiety onto the drug or its vehicle to aim for upregulated target proteins at the target site when compared to other sites of the body.8 GAPDH is a suitable protein target as it has been recently found on the cell surface of M. TB and also involves in internalising iron-bearing proteins.9 If such internalisations can be applied similarly to antituberculosis drugs by means of conjugation with GAPDH targeting agents, this could lead to a new direction in the development of future treatment for TB.
This research aims to discover the active small molecules that target GAPDH and eventually enhance the delivery of antituberculosis drugs directly against M. TB using molecular docking studies. Ten compounds with previously reported in vitro and/or in vivo activities against GAPDH or used as targeting agents were assessed for their binding affinity through molecular docking technique using AutoDock 4.2. In molecular docking, many possible orientations of a compound were generated at the binding site of a target protein and the orientation with the lowest binding energy is predicted to possess the best mode of binding to the binding site of the protein.10 Among the 10 ligands, curcumin, koningic acid and folic acid were discovered to possess the best binding affinity with GAPDH. Folic acid was chosen to be further studied as its binding profile with GAPDH has never been reported before despite being a popular targeting agent for anticancer drugs. 13 derivatives of folic acid were then docked against GAPDH. F7 (folic acid N-hydroxysuccinimide) and F8 (ester γ-{[tert-butyl-N-(2-aminohexyl)]carbamate}folic acid) were found to have most favourable binding energy amongst the folic acid derivatives due to the addition of a bulky group which lead to additional van der Waals forces. In conclusion, folic acid and F7 have the potential to be further developed as targeting agents against the GAPDH receptor.
Contributed: Muhammad Amirul Asyraf bin Noh
Source: https://www.degruyter.com/document/doi/10.1515/jbcpp-2020-0435/html\
Superimposed docked model of all 10 selected ligands and NAD (the co-crystallized ligand) at the NAD binding domain of GAPDH. Image created with BIOVIA Discovery Studio 2019 (BIOVIA & Dassault Systèmes, 2019).
References:
1. WHO. Global Tuberculosis Report 2021.; 2021. https://www.who.int/publications/digital/global-tuberculosis-report-2021
2. Horsburgh CR, Barry CE, Lange C. Treatment of Tuberculosis. N Engl J Med. 2015;373(22):2149-2160. doi:10.1056/NEJMra1413919
3. Mazlan MKN, Mohd Tazizi MHD, Ahmad R, et al. Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach. Antibiotics. 2021;10(8). doi:10.3390/antibiotics10080908
4. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59(8):748-758. doi:10.1016/j.addr.2007.06.008
5. Kazi KM, Mandal AS, Biswas N, et al. Niosome: A future of targeted drug delivery systems. J Adv Pharm Technol Res. 2010;1(4):374-380. doi:10.4103/0110-5558.76435
6. Manish G, Vimukta S. Targeted drug delivery system: A Review. In: ; 2011.
7. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135-146. doi:https://doi.org/10.1016/j.jconrel.2010.08.027
8. Clemons TD, Singh R, Sorolla A, Chaudhari N, Hubbard A, Iyer KS. Distinction Between Active and Passive Targeting of Nanoparticles Dictate Their Overall Therapeutic Efficacy. Langmuir. 2018;34(50):15343-15349. doi:10.1021/acs.langmuir.8b02946
9. Boradia VM, Malhotra H, Thakkar JS, et al. Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin. Nat Commun. 2014;5:4730. doi:10.1038/ncomms5730
10. Gagic Z, Ruzic D, Djokovic N, Djikic T, Nikolic K. In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs. Front Chem. 2020;7. doi:10.3389/fchem.2019.00873
Targeted drug delivery focused on increasing the amount of drug uptake at the target sites while decreasing the drug concentration at the non-target sites.4 Consequently, the drug is able to display its maximum effectiveness and exhibit fewer side effects due to lesser drug loss to non-target sites.5,6 Targeted drug delivery is categorised into two main types: passive and active drug targeting. Passive targeting involves taking advantage of the changed environment of the targeted cells such as loosen blood vasculature and cell junction caused by the disease itself,7 active targeting involves conjugating a targeting moiety onto the drug or its vehicle to aim for upregulated target proteins at the target site when compared to other sites of the body.8 GAPDH is a suitable protein target as it has been recently found on the cell surface of M. TB and also involves in internalising iron-bearing proteins.9 If such internalisations can be applied similarly to antituberculosis drugs by means of conjugation with GAPDH targeting agents, this could lead to a new direction in the development of future treatment for TB.
This research aims to discover the active small molecules that target GAPDH and eventually enhance the delivery of antituberculosis drugs directly against M. TB using molecular docking studies. Ten compounds with previously reported in vitro and/or in vivo activities against GAPDH or used as targeting agents were assessed for their binding affinity through molecular docking technique using AutoDock 4.2. In molecular docking, many possible orientations of a compound were generated at the binding site of a target protein and the orientation with the lowest binding energy is predicted to possess the best mode of binding to the binding site of the protein.10 Among the 10 ligands, curcumin, koningic acid and folic acid were discovered to possess the best binding affinity with GAPDH. Folic acid was chosen to be further studied as its binding profile with GAPDH has never been reported before despite being a popular targeting agent for anticancer drugs. 13 derivatives of folic acid were then docked against GAPDH. F7 (folic acid N-hydroxysuccinimide) and F8 (ester γ-{[tert-butyl-N-(2-aminohexyl)]carbamate}folic acid) were found to have most favourable binding energy amongst the folic acid derivatives due to the addition of a bulky group which lead to additional van der Waals forces. In conclusion, folic acid and F7 have the potential to be further developed as targeting agents against the GAPDH receptor.
Contributed: Muhammad Amirul Asyraf bin Noh
Source: https://www.degruyter.com/document/doi/10.1515/jbcpp-2020-0435/html\
Superimposed docked model of all 10 selected ligands and NAD (the co-crystallized ligand) at the NAD binding domain of GAPDH. Image created with BIOVIA Discovery Studio 2019 (BIOVIA & Dassault Systèmes, 2019).
References:
1. WHO. Global Tuberculosis Report 2021.; 2021. https://www.who.int/publications/digital/global-tuberculosis-report-2021
2. Horsburgh CR, Barry CE, Lange C. Treatment of Tuberculosis. N Engl J Med. 2015;373(22):2149-2160. doi:10.1056/NEJMra1413919
3. Mazlan MKN, Mohd Tazizi MHD, Ahmad R, et al. Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach. Antibiotics. 2021;10(8). doi:10.3390/antibiotics10080908
4. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59(8):748-758. doi:10.1016/j.addr.2007.06.008
5. Kazi KM, Mandal AS, Biswas N, et al. Niosome: A future of targeted drug delivery systems. J Adv Pharm Technol Res. 2010;1(4):374-380. doi:10.4103/0110-5558.76435
6. Manish G, Vimukta S. Targeted drug delivery system: A Review. In: ; 2011.
7. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135-146. doi:https://doi.org/10.1016/j.jconrel.2010.08.027
8. Clemons TD, Singh R, Sorolla A, Chaudhari N, Hubbard A, Iyer KS. Distinction Between Active and Passive Targeting of Nanoparticles Dictate Their Overall Therapeutic Efficacy. Langmuir. 2018;34(50):15343-15349. doi:10.1021/acs.langmuir.8b02946
9. Boradia VM, Malhotra H, Thakkar JS, et al. Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin. Nat Commun. 2014;5:4730. doi:10.1038/ncomms5730
10. Gagic Z, Ruzic D, Djokovic N, Djikic T, Nikolic K. In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs. Front Chem. 2020;7. doi:10.3389/fchem.2019.00873