{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:16:13Z","timestamp":1784229373279,"version":"3.55.0"},"reference-count":113,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: 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. Methods: 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\u2019s 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. Results: The docking yielded 155 compounds meeting the stringent criteria of \u22128.9 kcal\/mol instead of the widely used \u22127.0 kcal\/mol. These compounds demonstrated binding affinities comparable to the known inhibitors; methotrexate (\u22129.5 kcal\/mol), jatrorrhizine (\u22129.0 kcal\/mol), pyrimethamine (\u22127.3 kcal\/mol), hardwickiic acid (\u22128.1 kcal\/mol), and columbamine (\u22128.6 kcal\/mol). Protein\u2013ligand 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 (Leishmania) with Pa values of 0.642, 0.297, 0.543, 0.431, and 0.350, respectively. Conclusions: 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\u2013Boltzmann surface area (MM\/PBSA) calculations confirmed the robust binding interactions and provided insights into the dynamics and stability of the protein\u2013ligand complexes.<\/jats:p>","DOI":"10.3390\/ph18010006","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T09:48:58Z","timestamp":1735033738000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Natural Product Identification and Molecular Docking Studies of Leishmania Major Pteridine Reductase Inhibitors"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8760-4407","authenticated-orcid":false,"given":"Moses N.","family":"Arthur","sequence":"first","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra P.O. Box LG 581, Ghana"},{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra P.O. Box LG 581, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6793-7530","authenticated-orcid":false,"given":"Emmanuel","family":"Broni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick O.","family":"Sakyi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 56, Ghana"},{"name":"Department of Chemical Sciences, School of Sciences, University of Energy and Natural Resources, Sunyani P.O. Box 214, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrietta","family":"Mensah-Brown","sequence":"additional","affiliation":[{"name":"West 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, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-7940","authenticated-orcid":false,"suffix":"III","given":"Whelton A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA"},{"name":"Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1517","authenticated-orcid":false,"given":"Samuel K.","family":"Kwofie","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yizengaw, E., Gashaw, B., Yimer, M., Takele, Y., Nibret, E., Yismaw, G., Cruz Cervera, E., Ejigu, K., Tamiru, D., and Munshea, A. (2024). Demographic Characteristics and Clinical Features of Patients Presenting with Different Forms of Cutaneous Leishmaniasis, in Lay Gayint, Northern Ethiopia. PLoS Negl. Trop. Dis., 18.","DOI":"10.1101\/2024.02.15.24302809"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nawattanapaibool, N., Ruang-Areerate, T., Piyaraj, P., Leelayoova, S., Mungthin, M., and Siripattanapipong, S. (2024). Development of Nucleic Acid Lateral Flow Immunoassay for Duplex Detection of Leishmania Martiniquensis and Leishmania Orientalis in Asymptomatic Patients with HIV. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0307601"},{"key":"ref_3","unstructured":"WHO (2021). Leishmaniasis, WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1515\/jtim-2015-0002","article-title":"Leishmaniasis Revisited: Current Aspects on Epidemiology, Diagnosis and Treatment","volume":"3","author":"Georgiadou","year":"2015","journal-title":"J. Transl. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Alvar, J., V\u00e9lez, I.D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., and de Boer, M. (2012). Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035671"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Costa-da-Silva, A.C., Nascimento, D.d.O., Ferreira, J.R.M., Guimar\u00e3es-Pinto, K., Freire-de-Lima, L., Morrot, A., Decote-Ricardo, D., Filardy, A.A., and Freire-de-Lima, C.G. (2022). Immune Responses in Leishmaniasis: An Overview. Trop. Med. Infect. Dis., 7.","DOI":"10.3390\/tropicalmed7040054"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4103\/0974-777X.62863","article-title":"A Current Perspective on Leishmaniasis","volume":"2","author":"Clem","year":"2010","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s44197-024-00190-z","article-title":"Global Dilemma and Needs Assessment Toward Achieving Sustainable Development Goals in Controlling Leishmaniasis","volume":"14","author":"Bamorovat","year":"2024","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Knight, C.A., Harris, D.R., Alshammari, S.O., Gugssa, A., Young, T., and Lee, C.M. (2023). Leishmaniasis: Recent Epidemiological Studies in the Middle East. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.1052478"},{"key":"ref_10","unstructured":"Almeida-Souza, F., Cardoso, F.d.O., Abreu-Silva, A.L., and Calabrese, K.d.S. (2024). Epidemiology of Leishmaniasis, IntechOpen. Chapter 2."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.4269\/ajtmh.15-0408","article-title":"Social and Economic Burden of Human Leishmaniasis","volume":"94","author":"Okwor","year":"2016","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2147\/DDDT.S146521","article-title":"Leishmaniasis in Humans: Drug or Vaccine Therapy?","volume":"12","author":"Ghorbani","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_13","first-page":"9","article-title":"Current Treatment of Leishmaniasis: A Review","volume":"1","author":"Monzote","year":"2009","journal-title":"Open Antimicrob. Agents J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S1995-7645(12)60084-4","article-title":"Leishmaniasis: Current Status of Available Drugs and New Potential Drug Targets","volume":"5","author":"Singh","year":"2012","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ol\u00edas-Molero, A.I., de la Fuente, C., Cuquerella, M., Torrado, J.J., and Alunda, J.M. (2021). Antileishmanial Drug Discovery and Development: Time to Reset the Model?. Microorganisms, 9.","DOI":"10.3390\/microorganisms9122500"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wise, E.S., Armstrong, M.S., Watson, J., and Lockwood, D.N. (2012). Monitoring Toxicity Associated with Parenteral Sodium Stibogluconate in the Day-Case Management of Returned Travellers with New World Cutaneous Leishmaniasis [Corrected]. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/annotation\/15ab4f39-31e7-40bc-9b15-6e90a612b49a"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic Review of the Adverse Effects of Cutaneous Leishmaniasis Treatment in the New World","volume":"118","author":"Oliveira","year":"2011","journal-title":"Acta Trop."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chanda, K. (2021). An Overview on the Therapeutics of Neglected Infectious Diseases-Leishmaniasis and Chagas Diseases. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.622286"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8629039","DOI":"10.1155\/2021\/8629039","article-title":"Efficacy and Safety of Paromomycin for Visceral Leishmaniasis: A Systematic Review","volume":"2021","author":"Pokharel","year":"2021","journal-title":"J. Trop. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1093\/cid\/civ004","article-title":"Miltefosine for Visceral and Cutaneous Leishmaniasis: Drug Characteristics and Evidence-Based Treatment Recommendations","volume":"60","author":"Saravolatz","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41579-022-00777-y","article-title":"Anti-Trypanosomatid Drug Discovery: Progress and Challenges","volume":"21","author":"Wyllie","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4103\/2231-4040.104709","article-title":"Natural Products Derived from Plants as a Source of Drugs","volume":"3","author":"Veeresham","year":"2012","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_23","first-page":"1","article-title":"Plant-Derived Compounds in Treatment of Leishmaniasis","volume":"16","author":"Oryan","year":"2015","journal-title":"Iran. J. Vet. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Di Pisa, F., Landi, G., Dello Iacono, L., Pozzi, C., Borsari, C., Ferrari, S., Santucci, M., Santarem, N., Cordeiro-da-Silva, A., and Moraes, C.B. (2017). Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules, 22.","DOI":"10.3390\/molecules22030426"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13065-023-01111-0","article-title":"Synthesis, Antileishmanial, Antimalarial Evaluation and Molecular Docking Study of Some Hydrazine-Coupled Pyrazole Derivatives","volume":"18","author":"Berhe","year":"2024","journal-title":"BMC Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.ejmech.2017.03.043","article-title":"An Integrated Approach towards the Discovery of Novel Non-Nucleoside Leishmania Major Pteridine Reductase 1 Inhibitors","volume":"132","author":"Leite","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ejmech.2016.07.060","article-title":"Structure-Guided Discovery of Thiazolidine-2,4-Dione Derivatives as a Novel Class of Leishmania Major Pteridine Reductase 1 Inhibitors","volume":"123","author":"Leite","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1017\/S0031182097001133","article-title":"New Approaches to Leishmania Chemotherapy: Pteridine Reductase 1 (PTR1) as a Target and Modulator of Antifolate Sensitivity","volume":"114","author":"Nare","year":"1997","journal-title":"Parasitology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/88584","article-title":"Pteridine Reductase Mechanism Correlates Pterin Metabolism with Drug Resistance in Trypanosomatid Parasites","volume":"8","author":"Gourley","year":"2001","journal-title":"Nat. Struct. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e24599","DOI":"10.1002\/jcla.24599","article-title":"Global Distribution of Treatment Resistance Gene Markers for Leishmaniasis","volume":"36","author":"Salari","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1107\/S2053230X22002795","article-title":"Crystal Structure of the Ternary Complex of Leishmania Major Pteridine Reductase 1 with the Cofactor NADP+\/NADPH and the Substrate Folic Acid","volume":"78","author":"Iacono","year":"2022","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1177\/1087057114555846","article-title":"High-Throughput Screening Platform for Natural Product-Based Drug Discovery against 3 Neglected Tropical Diseases: Human African Trypanosomiasis, Leishmaniasis, and Chagas Disease","volume":"20","author":"Annang","year":"2015","journal-title":"J. Biomol. Screen."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7598","DOI":"10.1021\/acs.jmedchem.6b00698","article-title":"Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs","volume":"59","author":"Borsari","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3989","DOI":"10.1021\/acs.jmedchem.8b02021","article-title":"Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections","volume":"62","author":"Linciano","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4618","DOI":"10.1080\/07391102.2020.1779129","article-title":"In Silico Identification of Potential Inhibitors from Cinnamon against Main Protease and Spike Glycoprotein of SARS CoV-2","volume":"39","author":"Prasanth","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8772","DOI":"10.3390\/molecules20058772","article-title":"Development and Validation of a Docking-Based Virtual Screening Platform for the Identification of New Lactate Dehydrogenase Inhibitors","volume":"20","author":"Granchi","year":"2015","journal-title":"Molecules"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jmgm.2010.05.005","article-title":"LigAlign: Flexible Ligand-Based Active Site Alignment and Analysis","volume":"29","author":"Heifets","year":"2010","journal-title":"J. Mol. Graph. Model."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.3390\/molecules19021672","article-title":"Docking Studies in Target Proteins Involved in Antibacterial Action Mechanisms: Extending the Knowledge on Standard Antibiotics to Antimicrobial Mushroom Compounds","volume":"19","author":"Alves","year":"2014","journal-title":"Molecules"},{"key":"ref_40","first-page":"627","article-title":"Receiver Operating Characteristic (ROC) Curve Analysis for Medical Diagnostic Test Evaluation","volume":"4","year":"2013","journal-title":"Casp. J. Intern. Med."},{"key":"ref_41","first-page":"1934578X211031148","article-title":"Antileishmanial Potential of Berberine Alkaloids From Berberis Glaucocarpa Roots: Molecular Docking Suggests Relevant Leishmania Protein Targets","volume":"16","author":"Alamzeb","year":"2021","journal-title":"Nat. Prod. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00249-023-01677-6","article-title":"Structure and Dynamics of Pteridine Reductase 1: The Key Phenomena Relevant to Enzyme Function and Drug Design","volume":"52","author":"Poehner","year":"2023","journal-title":"Eur. Biophys. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1111\/j.1365-2958.2006.05332.x","article-title":"Structure and Reactivity of Trypanosoma Brucei Pteridine Reductase: Inhibition by the Archetypal Antifolate Methotrexate","volume":"61","author":"Dawson","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Crentsil, J.A., Yamthe, L.R.T., Anibea, B.Z., Broni, E., Kwofie, S.K., Tetteh, J.K.A., and Osei-Safo, D. (2020). Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton Sylvaticus. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00753"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.32614\/RJ-2016-042","article-title":"EasyROC: An Interactive Web-Tool for Roc Curve Analysis Using r Language Environment","volume":"8","author":"Goksuluk","year":"2016","journal-title":"R J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Possart, K., Herrmann, F.C., Jose, J., and Schmidt, T.J. (2023). In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma Brucei and Leishmania Major Pteridine Reductase 1 and Dihydrofolate Reductase. Molecules, 28.","DOI":"10.3390\/molecules28227526"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Herrmann, F.C., Sivakumar, N., Jose, J., Costi, M.P., Pozzi, C., and Schmidt, T.J. (2017). In Silico Identification and in Vitro Evaluation of Natural Inhibitors of Leishmania Major Pteridine Reductase I. Molecules, 22.","DOI":"10.3390\/molecules22122166"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Al Nasr, I.S., Hanachi, R., Said, R.B., Rahali, S., Tangour, B., Abdelwahab, S.I., Farasani, A., Taha, M.M.E., Bidwai, A., and Koko, W.S. (2021). P-Trifluoromethyl- and p-Pentafluorothio-Substituted Curcuminoids of the 2,6-Di[(E)-Benzylidene)]Cycloalkanone Type: Syntheses and Activities against Leishmania Major and Toxoplasma Gondii Parasites. Bioorg. Chem., 114.","DOI":"10.1016\/j.bioorg.2021.105099"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1021\/ci700044s","article-title":"Analysis of HIV Wild-Type and Mutant Structures via in Silico Docking against Diverse Ligand Libraries","volume":"47","author":"Chang","year":"2007","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","first-page":"30","article-title":"New Benzimidazole Derivatives as Inhibitors of Pteridine Reductase 1: Design, Molecular Docking Study and ADMET Prediction","volume":"10","author":"Phadke","year":"2020","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1073\/pnas.0704384105","article-title":"Discovery of Potent Pteridine Reductase Inhibitors to Guide Antiparasite Drug Development","volume":"105","author":"Cavazzuti","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1039\/C8MD00472B","article-title":"ADMET-Score-a Comprehensive Scoring Function for Evaluation of Chemical Drug-Likeness","volume":"10","author":"Guan","year":"2019","journal-title":"Medchemcomm"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.drudis.2019.10.014","article-title":"A Drug-Likeness Toolbox Facilitates ADMET Study in Drug Discovery","volume":"25","author":"Jia","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.addr.2016.04.029","article-title":"Rule of Five in 2015 and beyond: Target and Ligand Structural Limitations, Ligand Chemistry Structure and Drug Discovery Project Decisions","volume":"101","author":"Lipinski","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1021\/jm0492002","article-title":"A Bioavailability Score","volume":"48","author":"Martin","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Loftsson, T. (2015). Physicochemical Properties and Pharmacokinetics. Essent. Pharmacokinet., 85\u2013104.","DOI":"10.1016\/B978-0-12-801411-0.00003-2"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Bohnert, T., and Prakash, C. (2012). ADME Profiling in Drug Discovery and Development: An Overview. Encycl. Drug Metab. Interact., 1\u201342.","DOI":"10.1002\/9780470921920.edm021"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2165\/00003088-200342020-00004","article-title":"Strategies and Molecular Probes to Investigate the Role of Cytochrome P450 in Drug Metabolism: Focus on in Vitro Studies","volume":"42","author":"Donato","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1166\/jbns.2018.1505","article-title":"Molecular Docking Studies and ADMET Properties of New 1.2.3 Triazole Derivatives for Anti-Breast Cancer Activity","volume":"12","author":"Ouassaf","year":"2018","journal-title":"J. Bionanoscience"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"277","DOI":"10.6026\/97320630015277","article-title":"Molecular Docking and Pharmacokinetic Evaluation of Natural Compounds as Targeted Inhibitors against Crz1 Protein in Rhizoctonia Solani","volume":"15","author":"Malik","year":"2019","journal-title":"Bioinformation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s11481-006-9025-3","article-title":"Blood-Brain Barrier: Structural Components and Function under Physiologic and Pathologic Conditions","volume":"1","author":"Persidsky","year":"2006","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"137","DOI":"10.18773\/austprescr.2014.050","article-title":"P-Glycoprotein and Its Role in Drug-Drug Interactions","volume":"37","author":"Finch","year":"2014","journal-title":"Aust. Prescr."},{"key":"ref_64","first-page":"2205","article-title":"Design, Molecular Docking and ADMET Studies of 2- Substituted-5-[ (1H-Benzimidazol-2yl) Methyl] 1,3,4- Oxadiazole Derivatives as Pteridine Reductase 1 Inhibitors","volume":"13","author":"Phadke","year":"2021","journal-title":"Int. J. Pharm. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mcree, D.E. (1999). 3\u2014Computational Techniques, Academic Press. [2nd ed.].","DOI":"10.1016\/B978-012486052-0\/50005-1"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13030-qt45r512w0","DOI":"10.5070\/D3206022861","article-title":"Cantharidin: A Comprehensive Review of the Clinical Literature","volume":"20","author":"Torbeck","year":"2014","journal-title":"Dermatol. Online J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.exppara.2010.04.004","article-title":"Leishmania Major: In Vitro and in Vivo Anti-Leishmanial Effect of Cantharidin","volume":"126","author":"Ghaffarifar","year":"2010","journal-title":"Exp. Parasitol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1590\/abd1806-4841.20186415","article-title":"Treatment of Cutaneous Leishmaniasis with Thermotherapy in Brazil: An Efficacy and Safety Study","volume":"93","author":"Costa","year":"2018","journal-title":"An. Bras. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/B978-0-444-64179-3.00007-4","article-title":"Terpenoids as Emerging Therapeutic Agents: Cellular Targets and Mechanisms of Action against Protozoan Parasites","volume":"59","author":"Isah","year":"2018","journal-title":"Stud. Nat. Prod. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Teles, C.B.G., Moreira-Dill, L.S., Silva, A.d.A., Facundo, V.A., de Azevedo, W.F., da Silva, L.H.P., Motta, M.C.M., St\u00e1beli, R.G., and Silva-Jardim, I. (2015). A Lupane-Triterpene Isolated from Combretum leprosum Mart. Fruit Extracts That Interferes with the Intracellular Development of Leishmania (L.) Amazonensis in Vitro. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0681-9"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1124\/mol.111.072785","article-title":"Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase","volume":"80","author":"Chowdhury","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.phymed.2015.08.012","article-title":"Antileishmanial Activity and Trypanothione Reductase Effects of Terpenes from the Amazonian Species Croton Cajucara Benth (Euphorbiaceae)","volume":"22","author":"Lima","year":"2015","journal-title":"Phytomedicine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1590\/S0074-02762013000100010","article-title":"Antileishmanial Activity of Diterpene Acids in Copaiba Oil","volume":"108","author":"Izumi","year":"2013","journal-title":"Mem. Inst. Oswaldo Cruz."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4553","DOI":"10.1128\/IAI.66.9.4553-4556.1998","article-title":"Paclitaxel (Taxol)-Induced Killing of Leishmania Major in Murine Macrophages","volume":"66","author":"Doherty","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"392918","DOI":"10.1155\/2015\/392918","article-title":"Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12\/IL-1 \u03b2\/CNOS\/NO Pathway","volume":"2015","author":"Miranda","year":"2015","journal-title":"Mediators Inflamm."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Camargos, H.S., Moreira, R.A., Mendanha, S.A., Fernandes, K.S., Dorta, M.L., and Alonso, A. (2014). Terpenes Increase the Lipid Dynamics in the Leishmania Plasma Membrane at Concentrations Similar to Their IC50 Values. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104429"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1080\/13880209.2016.1224257","article-title":"Antiprotozoal Activity of Extracts and Isolated Triterpenoids of \u201ccarnauba\u201d (Copernicia Prunifera) Wax from Brazil","volume":"54","author":"Carvalho","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.3390\/molecules19055761","article-title":"Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus Terebinthifolius (Anacardiaceae): Structure\/Activity Relationships","volume":"19","author":"Morais","year":"2014","journal-title":"Molecules"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ijantimicag.2004.08.010","article-title":"In Vitro Activity of C20-Diterpenoid Alkaloid Derivatives in Promastigotes and Intracellular Amastigotes of Leishmania Infantum","volume":"25","author":"Hitos","year":"2005","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1039\/b916679c","article-title":"Diterpenoid Alkaloids","volume":"27","author":"Wang","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/bioinformatics\/16.8.747","article-title":"PASS: Prediction of Activity Spectra for Biologically Active Substances","volume":"16","author":"Lagunin","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1007\/s00044-010-9398-y","article-title":"PASS-Assisted Exploration of New Therapeutic Potential of Natural Products","volume":"20","author":"Goel","year":"2010","journal-title":"Med. Chem. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0009-2797(02)00164-3","article-title":"Short-Chain Dehydrogenases\/Reductases (SDR): The 2002 Update","volume":"143\u2013144","author":"Oppermann","year":"2003","journal-title":"Chem. Biol. Interact."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2174\/1568026620666200128160454","article-title":"Outwitting an Old Neglected Nemesis: A Review on Leveraging Integrated Data-Driven Approaches to Aid in Unraveling of Leishmanicides of Therapeutic Potential","volume":"20","author":"Kwofie","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_85","first-page":"1","article-title":"Leishmania Proteomics: An in Silico Perspective","volume":"4","author":"Padilla","year":"2019","journal-title":"Preprints"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1056\/NEJMoa011882","article-title":"Fluconazole for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania Major","volume":"346","author":"Alrajhi","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"De Macedo-Silva, S.T., Urbina, J.A., De Souza, W., and Rodrigues, J.C.F. (2013). In Vitro Activity of the Antifungal Azoles Itraconazole and Posaconazole against Leishmania Amazonensis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083247"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1093\/jac\/dky229","article-title":"In Vitro Antileishmanial Activity of Ravuconazole, a Triazole Antifungal Drug, as a Potential Treatment for Leishmaniasis","volume":"73","author":"Visbal","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1093\/jac\/dku069","article-title":"Activity of Anti-Cancer Protein Kinase Inhibitors against Leishmania Spp.","volume":"69","author":"Sanderson","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, \u00c1.P., Chamorro, P., Rodr\u00edguez, M.L., Miguel Del Corral, J.M., Garc\u00eda, P.A., Francesch, A., San Feliciano, A., and Castro, M.\u00c1. (2021). New Antineoplastic Naphthohydroquinones Attached to Labdane and Rearranged Diterpene Skeletons. Molecules, 26.","DOI":"10.3390\/molecules26020474"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"El-Dirany, R., Shahrour, H., Dirany, Z., Abdel-Sater, F., Gonzalez-Gaitano, G., Brandenburg, K., Martinez de Tejada, G., and Nguewa, P.A. (2021). Activity of Anti-Microbial Peptides (Amps) against Leishmania and Other Parasites: An Overview. Biomolecules, 11.","DOI":"10.3390\/biom11070984"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"433","DOI":"10.2174\/092986708783503221","article-title":"Anticancer Compounds as Leishmanicidal Drugs: Challenges in Chemotherapy and Future Perspectives","volume":"15","author":"Perez","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_93","first-page":"154","article-title":"An Overview on Anticancer Drugs with Antileishmanial Activity","volume":"28","author":"Keighobadi","year":"2018","journal-title":"J. Maz. Univ. Med. Sci."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Wang, C., Greene, D., Xiao, L., Qi, R., and Luo, R. (2018). Recent Developments and Applications of the MMPBSA Method. Front. Mol. Biosci., 4.","DOI":"10.3389\/fmolb.2017.00087"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Kwofie, S.K., Hanson, G., Sasu, H., Enninful, K.S., Mensah, F.A., Nortey, R.T., Yeboah, O.P., Agoni, C., and Wilson, M.D. (2022). Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb. Chem. Biodivers., 19.","DOI":"10.1002\/cbdv.202200160"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Intakhan, N., Saeung, A., Rodrigues Oliveira, S.M., Pereira, M.d.L., and Chanmol, W. (2024). Synergistic Effects of Artesunate in Combination with Amphotericin B and Miltefosine against Leishmania Infantum: Potential for Dose Reduction and Enhanced Therapeutic Strategies. Antibiotics, 13.","DOI":"10.3390\/antibiotics13090806"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1107\/S0907444904018955","article-title":"Inhibition of Leishmania Major Pteridine Reductase by 2,4,6- Triaminoquinazoline: Structure of the NADPH Ternary Complex","volume":"60","author":"McLuskey","year":"2004","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_99","first-page":"169","article-title":"Gromacs 5.0.7","volume":"12","author":"Chauhan","year":"2011","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_100","unstructured":"Lindahl, A., and Hess, V.D.S. (2021). GROMACS Documentation. GROMACS 2021.3 Man., 1\u2013623."},{"key":"ref_101","unstructured":"DeLano, W.L. (2004). PyMOL User\u2019s Guide, DeLano Scientific LLC."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX: Meeting Modern Challenges in Visualization and Analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-Molecule Library Screening by Docking with PyRx","volume":"1263","author":"Dallakyan","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"166","DOI":"10.9734\/jpri\/2021\/v33i29A31575","article-title":"Design and In Silico Studies of 2,5-Disubstituted 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Pteridine Reductase 1 Inhibitors","volume":"33","author":"Phadke","year":"2021","journal-title":"J. Pharm. Res. Int."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An Open-Source Program for Chemistry Aware Data Visualization and Analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery","volume":"51","author":"RA","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1021\/jm300687e","article-title":"Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking","volume":"55","author":"Mysinger","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1007\/s11172-017-1954-x","article-title":"Computational Platform Way2Drug: From the Prediction of Biological Activity to Drug Repurposing","volume":"66","author":"Druzhilovskiy","year":"2018","journal-title":"Russ. Chem. Bull."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/s10593-014-1496-1","article-title":"Prediction of the Biological Activity Spectra of Organic Compounds Using the Pass Online Web Resource","volume":"50","author":"Filimonov","year":"2014","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible, and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Musyoka, T.M., Kanzi, A.M., Lobb, K.A., and Tastan Bishop, \u00d6. (2016). Structure Based Docking and Molecular Dynamic Studies of Plasmodial Cysteine Proteases against a South African Natural Compound and Its Analogs. Sci. Rep., 6.","DOI":"10.1038\/srep23690"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/1\/6\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:59:16Z","timestamp":1760115556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/1\/6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,24]]},"references-count":113,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ph18010006"],"URL":"https:\/\/doi.org\/10.3390\/ph18010006","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,24]]}}}