In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs

Dauda Garba; Jimoh Yusuf; Akande Amatul-Hafeez; Hassan Lukman Ali; Yakubu Muhammad Shamsudeen; Gidado Ibrahim; Rabiu Hafsat; Ismail Surayya Ibrahim; Tijani Omolara Tawakaltu; Olaiya Ayodele Akeem

doi:doi:10.11648/j.jddmc.20241003.11

Research Article |

| Peer-Reviewed

In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs

Dauda Garba^*

, Jimoh Yusuf

, Akande Amatul-Hafeez

, Hassan Lukman Ali

, Yakubu Muhammad Shamsudeen

, Gidado Ibrahim

, Rabiu Hafsat

, Ismail Surayya Ibrahim

, Tijani Omolara Tawakaltu

, Olaiya Ayodele Akeem

Published in Journal of Drug Design and Medicinal Chemistry (Volume 10, Issue 3)

Received: 8 August 2024 Accepted: 2 September 2024 Published: 30 September 2024

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from Globimetula oreophila on plasmepsin I and II, falciparum 2 and 3, Plasmodium falciparum calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against PfDHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.

Published in	Journal of Drug Design and Medicinal Chemistry (Volume 10, Issue 3)
DOI	10.11648/j.jddmc.20241003.11
Page(s)	67-80
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Globimetula oreophila, In-silico, Malaria, Plasmodium falciparum

References

[1]	World Health Organization. World Malaria Report (2022); World Health Organization: Geneva, Switzerland, 2022.
[2]	Smyth JD (1994) Animal Parasitology. Cambridge University Press, New York, p. 549.
[3]	Burkill HM (1985) The useful plants of West Tropical Africa vol. 4 Royal Botanical Gardens, Kew, Richmond UK. ISBN 9780947643010.
[4]	Dauda G, Haruna AK, Musa AM, Hassan B, Mohammed IM, Magaji MG (2016) In-vivo antimalarial activity of ethanol leaf extract of Globimetula oreophila (Hook. F) Danser Azadirachta Indica. BioL Environ Sci J Trop 13: 55-59.
[5]	Dauda G, Ali BH, Muhammed SY, Muhammad MG, Ismail AM, Muhammad MA, Hassan HS (2023) Qualitative and quantitative phytochemical profiling of ethnomedicinal folklore plant-Globimetula oreophila. J Curr Biomed Res 3: 1407-26.
[6]	Dauda G, Ali BH, Muhammad SY, Muhammed MG, Muhammad MA, Hassan HS (2023b) Levels of trace metals content of crude ethanol leaf extract of Globimetula oreophila (Hook. f) Danser growing on Azadirachta indica using atomic absorption spectroscopy. J Curr Biomed Res 3: 1397-1406.
[7]	Coombs GH, Goldberg DE, Klemba M, Berry C, Kay J, Mottram JC (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol 17: 532-537.
[8]	Rosenthal PJ (2004) Cysteine proteases of malaria parasites. Int J Parasitol 34: 1489-1499.
[9]	Murata CE, Goldberg DE (2003) Plasmodium falciparum falcilysin: a metalloprotease with dual specificity. J BioL Chem 278: 38022-38028.
[10]	Eggleson KK, Duffin KL, Goldberg DE (1999) Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum. J Biol Chem 274: 32411-32417.
[11]	Withers-Martinez C, Jean L, Blackman MJ (2004) Subtilisin-like proteases of the malaria parasite. Mol Microbiol 53: 55-63.
[12]	Blackman MJ (2008) Malarial proteases and host cell egress: an 'emerging' cascade. Cell Microbiol 10: 1925-1934.
[13]	Makrynitsa GI, Lykouras M, Spyroulias GA, Matsoukas MT (2018) In silico Drug Design. In: eLS. John Wiley and Sons, Ltd: Chichester. pp 1-7.
[14]	Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30: 2785–2791.
[15]	Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25: 1605-1612.
[16]	Machin JM, Kantsadi AL, Vakonakis I (2019) The complex of Plasmodium falciparum falcipain-2 protease with an (E)-chalcone-based inhibitor highlights a novel, small, molecule-binding site. Malar J 18: 1-9.
[17]	Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009) Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity. J Med Chem 52: 852-857.
[18]	Bhaumik P, Horimoto Y, Xiao H, Miura T, Hidaka K, Kiso Y, Wlodawer A, Yada RY, Gustchina A (2011) Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum. J Struct BioL 175: 73-84.
[19]	Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM (2003) Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. J Mol Biol 327: 173-181.
[20]	Smith NA, Clarke OB, Lee M, Hodder AN, Smith BJ (2020) Structure of the Plasmodium falciparum PfSERA5 pseudo-zymogen. Prot Sci 29: 2245-2258.
[21]	Lauciello L, Pernot L, Bottegoni G, Bisson W, Scapozza L, Perozzo R (To be published) P. falciparum Calcium-Dependent Protein Kinase 2 (PfCDPK2): First Crystal Structure and Virtual Ligand Screening. https://www.rcsb.org/structure/4MVF
[22]	Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y (2005) Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance. Proc Natl Acad Sci 102: 13046-13051.
[23]	De Oliveira ME, Cenzi G, Nunes RR, Andrighetti CR, de Sousa Valadão DM, Dos Reis C, Simões CM, Nunes RJ, Júnior MC, Taranto AG, Sanchez BA (2013) Antimalarial activity of 4-metoxychalcones: Docking studies as falcipain/plasmepsin inhibitors, ADMET and lipophilic efficiency analysis to identify a putative oral lead candidate. Molecules 18: 15276-87.
[24]	Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five revolution. Drug discovery today: Tech 1: 337-341.
[25]	Ojo OA, Aruleba RT, Adekiya TA, Sibuyi NR, Ojo AB, Ajiboye BO, Oyinloye BE, Adeola H, Fadaka AO (2020) Deciphering the interaction of Puerarin with cancer macromolecules: an In-silico investigation. J Biomol Struct Dynam 2020. https://doi.org/10.1080/07391102.2020.1819425
[26]	Swierczewska M, Lee KC, Lee S (2015) What is the future of PEGylated therapies? Expet Opin Emerg Drugs 20: 531–6.
[27]	Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X, Lai L, Pei J, Li H (2017) PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res 45: 356-60.
[28]	Banerjee P, Kemmler E, Dunkel M, Preissner R (2024) ProTox 3.0: a web server for the prediction of toxicity of chemicals. Nucleic Acids Res.
[29]	Ojo OA, Ojo AB, Maimako RF, Rotimi D, Iyobhebhe M, Alejolowo O, Nwonuma CO, Elebiyo TC (2021) Exploring the potentials of some compounds from garcina kola seeds towards identification of novel PDE-5 inhibitors in erectile dysfunction therapy. Andrologia. https://doi.org/10.1111/and.14092
[30]	Ojo OA, Afon AA, Ojo AB, Ajiboye BO, Okesola MA, Aruleba RT, Adekiya TA, Oyinloye BE (2019) Spondias mombim L. (Anacardiaceae): chemical fingerprints, inhibitory activities and molecular docking on key enzymes relevant to erectile dysfunction and Alzheimer’s diseases. J Food Biochem 43: 12772. https://doi.org/10.1111/jfbc.12772
[31]	Cheng A, Dixon SL (2003) In silico models for the prediction of dose-dependent human hepatotoxicity. J Comput Aided Mol Des 17: 811–23.
[32]	Akar S, Çırak T, Hüsunet MT, Turkdonmez I, Kenger İH, Aslan F, Kardöl A, Yıldız H, Zencir S, Emek AG, Kayraldız A (2003) Determination of mutagenic potentials of diarylmethylamine based imine compounds by ames test and computational molecular docking. Exp AppL Med Sci 4: 610-20.
[33]	Nöteberg D, Schaal W, Hamelink E, Vrang L, Larhed M. High-speed optimization of inhibitors of the malarial proteases plasmepsin I and II (2003). J Comb Chem 5: 456-64.

Cite This Article

Plain Text BibTeX RIS

APA Style

Garba, D., Yusuf, J., Amatul-Hafeez, A., Ali, H. L., Shamsudeen, Y. M., et al. (2024). In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. Journal of Drug Design and Medicinal Chemistry, 10(3), 67-80. https://doi.org/10.11648/j.jddmc.20241003.11

Copy | Download

ACS Style

Garba, D.; Yusuf, J.; Amatul-Hafeez, A.; Ali, H. L.; Shamsudeen, Y. M., et al. In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. J. Drug Des. Med. Chem. 2024, 10(3), 67-80. doi: 10.11648/j.jddmc.20241003.11

Copy | Download

AMA Style

Garba D, Yusuf J, Amatul-Hafeez A, Ali HL, Shamsudeen YM, et al. In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. J Drug Des Med Chem. 2024;10(3):67-80. doi: 10.11648/j.jddmc.20241003.11

Copy | Download

@article{10.11648/j.jddmc.20241003.11,
  author = {Dauda Garba and Jimoh Yusuf and Akande Amatul-Hafeez and Hassan Lukman Ali and Yakubu Muhammad Shamsudeen and Gidado Ibrahim and Rabiu Hafsat and Ismail Surayya Ibrahim and Tijani Omolara Tawakaltu and Olaiya Ayodele Akeem},
  title = {In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs
},
  journal = {Journal of Drug Design and Medicinal Chemistry},
  volume = {10},
  number = {3},
  pages = {67-80},
  doi = {10.11648/j.jddmc.20241003.11},
  url = {https://doi.org/10.11648/j.jddmc.20241003.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jddmc.20241003.11},
  abstract = {Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from Globimetula oreophila on plasmepsin I and II, falciparum 2 and 3, Plasmodium falciparum calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against PfDHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.
},
 year = {2024}
}

Copy | Download

TY  - JOUR
T1  - In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs

AU  - Dauda Garba
AU  - Jimoh Yusuf
AU  - Akande Amatul-Hafeez
AU  - Hassan Lukman Ali
AU  - Yakubu Muhammad Shamsudeen
AU  - Gidado Ibrahim
AU  - Rabiu Hafsat
AU  - Ismail Surayya Ibrahim
AU  - Tijani Omolara Tawakaltu
AU  - Olaiya Ayodele Akeem
Y1  - 2024/09/30
PY  - 2024
N1  - https://doi.org/10.11648/j.jddmc.20241003.11
DO  - 10.11648/j.jddmc.20241003.11
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 67
EP  - 80
PB  - Science Publishing Group
SN  - 2472-3576
UR  - https://doi.org/10.11648/j.jddmc.20241003.11
AB  - Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from Globimetula oreophila on plasmepsin I and II, falciparum 2 and 3, Plasmodium falciparum calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against PfDHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.

VL  - 10
IS  - 3
ER  -

Copy | Download

Author Information

Dauda Garba

Department of Pharmaceutical and Medicinal Chemistry, University of Abuja, Abuja, Nigeria

Contact Email

http://orcid.org/0000-0002-5833-5511
Jimoh Yusuf

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0000-0001-9853-0314
Akande Amatul-Hafeez

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0009-2453-5732
Hassan Lukman Ali

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0006-6053-0259
Yakubu Muhammad Shamsudeen

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0007-9516-8269
Gidado Ibrahim

Department of Chemistry, Federal College of Education, Yola, Nigeria

Contact Email

http://orcid.org/0009-0000-7626-6110
Rabiu Hafsat

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0000-0001-9222-8042
Ismail Surayya Ibrahim

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0006-9384-8386
Tijani Omolara Tawakaltu

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0009-6378-0343
Olaiya Ayodele Akeem

Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University, Zaria, Nigeria

Contact Email

http://orcid.org/0009-0007-3080-4965

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Garba, D., Yusuf, J., Amatul-Hafeez, A., Ali, H. L., Shamsudeen, Y. M., et al. (2024). In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. Journal of Drug Design and Medicinal Chemistry, 10(3), 67-80. https://doi.org/10.11648/j.jddmc.20241003.11

Copy | Download

ACS Style

Garba, D.; Yusuf, J.; Amatul-Hafeez, A.; Ali, H. L.; Shamsudeen, Y. M., et al. In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. J. Drug Des. Med. Chem. 2024, 10(3), 67-80. doi: 10.11648/j.jddmc.20241003.11

Copy | Download

AMA Style

Garba D, Yusuf J, Amatul-Hafeez A, Ali HL, Shamsudeen YM, et al. In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs. J Drug Des Med Chem. 2024;10(3):67-80. doi: 10.11648/j.jddmc.20241003.11

Copy | Download

@article{10.11648/j.jddmc.20241003.11,
  author = {Dauda Garba and Jimoh Yusuf and Akande Amatul-Hafeez and Hassan Lukman Ali and Yakubu Muhammad Shamsudeen and Gidado Ibrahim and Rabiu Hafsat and Ismail Surayya Ibrahim and Tijani Omolara Tawakaltu and Olaiya Ayodele Akeem},
  title = {In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs
},
  journal = {Journal of Drug Design and Medicinal Chemistry},
  volume = {10},
  number = {3},
  pages = {67-80},
  doi = {10.11648/j.jddmc.20241003.11},
  url = {https://doi.org/10.11648/j.jddmc.20241003.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.jddmc.20241003.11},
  abstract = {Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from Globimetula oreophila on plasmepsin I and II, falciparum 2 and 3, Plasmodium falciparum calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against PfDHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.
},
 year = {2024}
}

Copy | Download

TY  - JOUR
T1  - In-Silico Screening of Prenylated Quercetin from Globimetula oreophila Against Plasmodium falciparum Enzymes: Hope for New Antimalarial Drugs

AU  - Dauda Garba
AU  - Jimoh Yusuf
AU  - Akande Amatul-Hafeez
AU  - Hassan Lukman Ali
AU  - Yakubu Muhammad Shamsudeen
AU  - Gidado Ibrahim
AU  - Rabiu Hafsat
AU  - Ismail Surayya Ibrahim
AU  - Tijani Omolara Tawakaltu
AU  - Olaiya Ayodele Akeem
Y1  - 2024/09/30
PY  - 2024
N1  - https://doi.org/10.11648/j.jddmc.20241003.11
DO  - 10.11648/j.jddmc.20241003.11
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 67
EP  - 80
PB  - Science Publishing Group
SN  - 2472-3576
UR  - https://doi.org/10.11648/j.jddmc.20241003.11
AB  - Malaria continues to be one of the most devastating global health problems due to the high morbidity and mortality it causes in endemic regions. The search for new antimalarial targets is vital because of the increasing prevalence of drug resistance in malaria parasites. Malarial proteases constitute promising therapeutic targets as they play important roles in the parasite life cycle. The inhibition of these enzymes has pharmacological and therapeutic significance since they are involved in numerous processes, including the development, invasion, egress, and breakdown of host hemoglobin to release amino acids for parasite sustenance. In this study, in silico techniques were used to shed light on the mechanisms underlying the inhibitory effects of prenylated quercetin isolated from Globimetula oreophila on plasmepsin I and II, falciparum 2 and 3, Plasmodium falciparum calcium-dependent protein kinase 2, dihydrofolate reductase-thymidylate synthase, and serine repeat antigen 5. The test compound significantly interacts with key enzyme binding pockets through hydrogen bonds, van der Waals, and hydrophobic interactions, influencing protease specificity control. Crucial ligand features like carbonyl and hydroxyl groups were identified as essential for receptor interactions. Comparative analysis revealed the test compound's strong binding affinities with energies ranging from -6.4 Kcal/mol to -9.4 Kcal/mol, indicating competitive potential against various enzymes, particularly excelling against PfDHFR-TS, plasmepsin-I, and SERA5 compared to native ligands. This suggests the compound's ability to competitively inhibit enzyme activity by targeting co-factor binding sites, especially with specific proteases, holding promise for therapeutic applications as potent inhibitors for the prevention and treatment of malaria.

VL  - 10
IS  - 3
ER  -

Copy | Download