Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors
<b>Background/Objectives</b>: Pteridine reductase 1 (PTR1) has been one of the prime targets for discovering novel antileishmanial therapeutics in the fight against Leishmaniasis. This enzyme catalyzes the NADPH-dependent reduction of pterins to their tetrahydro forms. While chemotherapy...
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2024-12-01
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| author | Moses N. Arthur George Hanson Emmanuel Broni Patrick O. Sakyi Henrietta Mensah-Brown Whelton A. Miller Samuel K. Kwofie |
| author_facet | Moses N. Arthur George Hanson Emmanuel Broni Patrick O. Sakyi Henrietta Mensah-Brown Whelton A. Miller Samuel K. Kwofie |
| author_sort | Moses N. Arthur |
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| description | <b>Background/Objectives</b>: Pteridine reductase 1 (PTR1) has been one of the prime targets for discovering novel antileishmanial therapeutics in the fight against Leishmaniasis. This enzyme catalyzes the NADPH-dependent reduction of pterins to their tetrahydro forms. While chemotherapy remains the primary treatment, its effectiveness is constrained by drug resistance, unfavorable side effects, and substantial associated costs. <b>Methods</b>: This study addresses the urgent need for novel, cost-effective drugs by employing in silico techniques to identify potential lead compounds targeting the PTR1 enzyme. A library of 1463 natural compounds from AfroDb and NANPDB, prefiltered based on Lipinski’s rules, was used to screen against the LmPTR1 target. The X-ray structure of LmPTR1 complexed with NADP and dihydrobiopterin (Protein Data Bank ID: 1E92) was identified to contain the critical residues Arg17, Leu18, Ser111, Phe113, Pro224, Gly225, Ser227, Leu229, and Val230 including the triad of residues Asp181-Tyr194-Lys198, which are critical for the catalytic process involving the reduction of dihydrofolate to tetrahydrofolate. <b>Results</b>: The docking yielded 155 compounds meeting the stringent criteria of −8.9 kcal/mol instead of the widely used −7.0 kcal/mol. These compounds demonstrated binding affinities comparable to the known inhibitors; methotrexate (−9.5 kcal/mol), jatrorrhizine (−9.0 kcal/mol), pyrimethamine (−7.3 kcal/mol), hardwickiic acid (−8.1 kcal/mol), and columbamine (−8.6 kcal/mol). Protein–ligand interactions and molecular dynamics (MD) simulation revealed favorable hydrophobic and hydrogen bonding with critical residues, such as Lys198, Arg17, Ser111, Tyr194, Asp181, and Gly225. Crucial to the drug development, the compounds were physiochemically and pharmacologically profiled, narrowing the selection to eight compounds, excluding those with potential toxicities. The five selected compounds ZINC000095486253, ZINC000095486221, ZINC000095486249, 8alpha-hydroxy-13-epi-pimar-16-en-6,18-olide, and pachycladin D were predicted to be antiprotozoal (<i>Leishmania</i>) with Pa values of 0.642, 0.297, 0.543, 0.431, and 0.350, respectively. <b>Conclusions</b>: This study identified five lead compounds that showed substantial binding affinity against LmPTR1 as well as critical residue interactions. A 100 ns MD combined with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations confirmed the robust binding interactions and provided insights into the dynamics and stability of the protein–ligand complexes. |
| format | Article |
| id | doaj-art-8dea198db8424743a86ff637c1f52e0a |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-8dea198db8424743a86ff637c1f52e0a2025-01-24T13:44:57ZengMDPI AGPharmaceuticals1424-82472024-12-01181610.3390/ph18010006Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase InhibitorsMoses N. Arthur0George Hanson1Emmanuel Broni2Patrick O. Sakyi3Henrietta Mensah-Brown4Whelton A. Miller5Samuel K. Kwofie6Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra P.O. Box LG 581, GhanaDepartment of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra P.O. Box LG 581, GhanaDepartment of Medicine, Loyola University Medical Center, Maywood, IL 60153, USADepartment of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 56, GhanaWest African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra P.O. Box LG 54, GhanaDepartment of Medicine, Loyola University Medical Center, Maywood, IL 60153, USADepartment of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana<b>Background/Objectives</b>: Pteridine reductase 1 (PTR1) has been one of the prime targets for discovering novel antileishmanial therapeutics in the fight against Leishmaniasis. This enzyme catalyzes the NADPH-dependent reduction of pterins to their tetrahydro forms. While chemotherapy remains the primary treatment, its effectiveness is constrained by drug resistance, unfavorable side effects, and substantial associated costs. <b>Methods</b>: This study addresses the urgent need for novel, cost-effective drugs by employing in silico techniques to identify potential lead compounds targeting the PTR1 enzyme. A library of 1463 natural compounds from AfroDb and NANPDB, prefiltered based on Lipinski’s rules, was used to screen against the LmPTR1 target. The X-ray structure of LmPTR1 complexed with NADP and dihydrobiopterin (Protein Data Bank ID: 1E92) was identified to contain the critical residues Arg17, Leu18, Ser111, Phe113, Pro224, Gly225, Ser227, Leu229, and Val230 including the triad of residues Asp181-Tyr194-Lys198, which are critical for the catalytic process involving the reduction of dihydrofolate to tetrahydrofolate. <b>Results</b>: The docking yielded 155 compounds meeting the stringent criteria of −8.9 kcal/mol instead of the widely used −7.0 kcal/mol. These compounds demonstrated binding affinities comparable to the known inhibitors; methotrexate (−9.5 kcal/mol), jatrorrhizine (−9.0 kcal/mol), pyrimethamine (−7.3 kcal/mol), hardwickiic acid (−8.1 kcal/mol), and columbamine (−8.6 kcal/mol). Protein–ligand interactions and molecular dynamics (MD) simulation revealed favorable hydrophobic and hydrogen bonding with critical residues, such as Lys198, Arg17, Ser111, Tyr194, Asp181, and Gly225. Crucial to the drug development, the compounds were physiochemically and pharmacologically profiled, narrowing the selection to eight compounds, excluding those with potential toxicities. The five selected compounds ZINC000095486253, ZINC000095486221, ZINC000095486249, 8alpha-hydroxy-13-epi-pimar-16-en-6,18-olide, and pachycladin D were predicted to be antiprotozoal (<i>Leishmania</i>) with Pa values of 0.642, 0.297, 0.543, 0.431, and 0.350, respectively. <b>Conclusions</b>: This study identified five lead compounds that showed substantial binding affinity against LmPTR1 as well as critical residue interactions. A 100 ns MD combined with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations confirmed the robust binding interactions and provided insights into the dynamics and stability of the protein–ligand complexes.https://www.mdpi.com/1424-8247/18/1/6natural productsmolecular dockingmolecular dynamics simulationsADMETMM/PBSA<i>Leishmania</i> |
| spellingShingle | Moses N. Arthur George Hanson Emmanuel Broni Patrick O. Sakyi Henrietta Mensah-Brown Whelton A. Miller Samuel K. Kwofie Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors Pharmaceuticals natural products molecular docking molecular dynamics simulations ADMET MM/PBSA <i>Leishmania</i> |
| title | Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors |
| title_full | Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors |
| title_fullStr | Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors |
| title_full_unstemmed | Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors |
| title_short | Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors |
| title_sort | natural product identification and molecular docking studies of leishmania major pteridine reductase inhibitors |
| topic | natural products molecular docking molecular dynamics simulations ADMET MM/PBSA <i>Leishmania</i> |
| url | https://www.mdpi.com/1424-8247/18/1/6 |
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