{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:08:46Z","timestamp":1770970126247,"version":"3.50.1"},"reference-count":98,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T00:00:00Z","timestamp":1573084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grand Challenges Africa Programme","award":["GCA\/DD\/rnd3\/023"],"award-info":[{"award-number":["GCA\/DD\/rnd3\/023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.<\/jats:p>","DOI":"10.3390\/molecules24224036","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T11:17:25Z","timestamp":1573125445000},"page":"4036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-9482","authenticated-orcid":false,"given":"Thommas","family":"Musyoka","sequence":"first","affiliation":[{"name":"Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6861-7849","authenticated-orcid":false,"given":"\u00d6zlem Tastan","family":"Bishop","sequence":"additional","affiliation":[{"name":"Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,7]]},"reference":[{"key":"ref_1","unstructured":"(2018). World Malaria Report 2018, World Health Organisation."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S1473-3099(15)70032-0","article-title":"Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: A cross-sectional survey of the K13 molecular marker","volume":"15","author":"Tun","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/infdis\/jiu491","article-title":"Independent Emergence of Artemisinin Resistance Mutations Among Plasmodium falciparum in Southeast Asia","volume":"211","author":"Jacob","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of Artemisinin Resistance in Plasmodium falciparum Malaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/nyas.12766","article-title":"Antimalarial drug resistance in Africa: Key lessons for the future","volume":"1342","author":"Laufer","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4269\/ajtmh.15-0007","article-title":"Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network","volume":"93","author":"Rosenthal","year":"2015","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1146\/annurev.micro.51.1.97","article-title":"Hemoglobin Metabolism in the Malaria Parasite Plasmodium Falciparum","volume":"51","author":"Francis","year":"2002","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_9","first-page":"207","article-title":"Plasmodial hemoglobin degradation: An ordered pathway in a specialized organelle","volume":"1","author":"Goldberg","year":"1992","journal-title":"Infect. Agents Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1111\/febs.14130","article-title":"Proteases as antimalarial targets: Strategies for genetic, chemical, and therapeutic validation","volume":"284","author":"Deu","year":"2017","journal-title":"FEBS J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1073\/pnas.1011560108","article-title":"Validation of isoleucine utilization targets in Plasmodium falciparum","volume":"108","author":"Goldberg","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8840","DOI":"10.1073\/pnas.0601876103","article-title":"Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems","volume":"103","author":"Gluzman","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","first-page":"481","article-title":"Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3","volume":"360","author":"Singh","year":"2015","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.molbiopara.2006.06.013","article-title":"Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum","volume":"150","author":"Sijwali","year":"2006","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4384","DOI":"10.1073\/pnas.0307720101","article-title":"Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum","volume":"101","author":"Sijwali","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Subramanian, S., Hardt, M., Choe, Y., Niles, R.K., Johansen, E.B., Legac, J., Gut, J., Kerr, I.D., Craik, C.S., and Rosenthal, P.J. (2009). Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005156"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/978-1-4419-8414-2_3","article-title":"Falcipains and other cysteine proteases of malaria parasites","volume":"712","author":"Rosenthal","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1042\/bj20031487","article-title":"Identification and biochemical characterization of vivapains, cysteine proteases of the malaria parasite Plasmodium vivax","volume":"378","author":"Pandey","year":"2004","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Prasad, R., Atul, P., Soni, A., Puri, S.K., and Sijwali, P.S. (2012). Expression, Characterization, and Cellular Localization of Knowpains, Papain-Like Cysteine Proteases of the Plasmodium knowlesi Malaria Parasite. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051619"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1111\/cmi.12124","article-title":"Plasmodium yoelii inhibitor of cysteine proteases is exported to exomembrane structures and interacts with yoelipain-2 during asexual blood-stage development","volume":"15","author":"Vaughan","year":"2013","journal-title":"Cell. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.exppara.2009.03.003","article-title":"Plasmodium chabaudi: Expression of active recombinant chabaupain-1 and localization studies in Anopheles sp.","volume":"122","author":"Martins","year":"2009","journal-title":"Exp. Parasitol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0166-6851(92)90209-3","article-title":"Isolation and characterization of a cysteine proteinase gene of Plasmodium falciparum","volume":"51","author":"Rosenthal","year":"1992","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29000","DOI":"10.1074\/jbc.M004459200","article-title":"Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum","volume":"275","author":"Shenai","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.2174\/092986711795328328","article-title":"Falcipains, Plasmodium falciparum cysteine proteases as key drug targets against malaria","volume":"18","author":"Teixeira","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1021\/jm8013663","article-title":"Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: Implications for substrate specificity","volume":"52","author":"Kerr","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12936-019-2790-2","article-title":"Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design","volume":"18","author":"Musyoka","year":"2019","journal-title":"Malar. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1080\/07391102.2015.1108231","article-title":"Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow","volume":"34","author":"Musyoka","year":"2016","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"408","DOI":"10.2174\/156802612799362913","article-title":"Falcipain inhibition as a promising antimalarial target","volume":"12","author":"Marco","year":"2012","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1093\/infdis\/jiy188","article-title":"Plasmodium falciparum Falcipain-2a Polymorphisms in Southeast Asia and Their Association With Artemisinin Resistance","volume":"218","author":"Siddiqui","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13321-015-0080-8","article-title":"SANCDB: A South African natural compound database","volume":"7","author":"Hatherley","year":"2015","journal-title":"J. Cheminform."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep23690","article-title":"Structure Based Docking and Molecular Dynamic Studies of Plasmodial Cysteine Proteases against a South African Natural Compound and its Analogs","volume":"6","author":"Musyoka","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.cell.2015.11.031","article-title":"A New Golden Age of Natural Products Drug Discovery","volume":"163","author":"Shen","year":"2015","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrd4510","article-title":"The re-emergence of natural products for drug discovery in the genomics era","volume":"14","author":"Harvey","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/med.21474","article-title":"Strategies to diversify natural products for drug discovery","volume":"38","author":"Li","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.4155\/fmc.10.299","article-title":"Extracting molecular information from African natural products to facilitate unique African-led drug-discovery efforts","volume":"3","author":"Chibale","year":"2011","journal-title":"Future Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Salas-Sarduy, E., Guerra, Y., Covaleda Cort\u00e9s, G., Avil\u00e9s, F., Ch\u00e1vez Planes, M., Salas-Sarduy, E., Guerra, Y., Covaleda Cort\u00e9s, G., Avil\u00e9s, F.X., and Ch\u00e1vez Planes, M.A. (2017). Identification of Tight-Binding Plasmepsin II and Falcipain 2 Inhibitors in Aqueous Extracts of Marine Invertebrates by the Combination of Enzymatic and Interaction-Based Assays. Mar. Drugs, 15.","DOI":"10.3390\/md15040123"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.bmcl.2014.01.074","article-title":"Identification of diverse natural products as falcipain-2 inhibitors through structure-based virtual screening","volume":"24","author":"Wang","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_38","first-page":"62","article-title":"Antiplasmodial activities of some abietane diterpenes from the leaves of Plectranthus species","volume":"104","author":"Khan","year":"2008","journal-title":"S. Afri. J. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.abb.2015.03.007","article-title":"Allosteric regulation of the Plasmodium falciparum cysteine protease falcipain-2 by heme","volume":"573","author":"Marques","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational methods in drug discovery","volume":"66","author":"Sliwoski","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/ddr.21222","article-title":"Computational Approaches for Drug Discovery","volume":"75","author":"Hung","year":"2014","journal-title":"Drug Dev. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/1097-0134(20010501)43:2<113::AID-PROT1023>3.0.CO;2-T","article-title":"High throughput docking for library design and library prioritization","volume":"43","author":"Diller","year":"2001","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ymeth.2014.08.001","article-title":"Virtual screening: An in silico tool for interlacing the chemical universe with the proteome","volume":"71","author":"Westermaier","year":"2015","journal-title":"Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/scientificamerican1000-82","article-title":"Better Decisions through Science","volume":"283","author":"Swets","year":"2000","journal-title":"Sci. Am."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00894-017-3253-8","article-title":"Docking-based virtual screening of Brazilian natural compounds using the OOMT as the pharmacological target database","volume":"23","author":"Carregal","year":"2017","journal-title":"J. Mol. Model."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s10822-013-9685-z","article-title":"Novel anti-plasmodial hits identified by virtual screening of the ZINC database","volume":"27","author":"Mugumbate","year":"2013","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Triballeau, N., Acher, F., Brabet, I., Pin, J.-P., and Bertrand, H.-O. (2004). Virtual Screening Workflow Development Guided by the \u201cReceiver Operating Characteristic\u201d Curve Approach. Application to High-Throughput Docking on Metabotropic Glutamate Receptor Subtype 4. J. Med. Chem.","DOI":"10.1021\/jm049092j"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Shityakov, S., F\u00f6rster, C., and Shityakov, S. (2014). In silico structure-based screening of versatile P-glycoprotein inhibitors using polynomial empirical scoring functions. Adv. Appl. Bioinforma. Chem., 7\u20138.","DOI":"10.2147\/AABC.S56046"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1021\/acs.jcim.6b00283","article-title":"Screening Explorer\u2212An Interactive Tool for the Analysis of Screening Results","volume":"56","author":"Zagury","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple Ligand\u2013Protein Interaction Diagrams for Drug Discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.2174\/0929867311320150008","article-title":"Profiling the Structural Determinants of Heteroarylnitrile Scaffold-Based Derivatives as Falcipain-2 Inhibitors by In Silico Methods","volume":"20","author":"Wang","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6129","DOI":"10.1021\/jm100556b","article-title":"Falcipain inhibitors: Optimization studies of the 2-pyrimidinecarbonitrile lead series","volume":"53","author":"Coteron","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1016\/j.bmcl.2011.09.107","article-title":"3D-QSAR and molecular docking studies of 2-pyrimidinecarbonitrile derivatives as inhibitors against falcipain-3","volume":"21","author":"Potshangbam","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.ejmech.2014.11.061","article-title":"Synthesis and structure\u2013activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2","volume":"90","author":"Sharma","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"D1202-13","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem Substance and Compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_56","unstructured":"(2018, August 22). MolPort. Available online: https:\/\/www.molport.com."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Lagorce, D., Sperandio, O., Galons, H., Miteva, M.A., and Villoutreix, B.O. (2008). FAF-Drugs2: Free ADME\/tox filtering tool to assist drug discovery and chemical biology projects. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-396"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1021\/acs.jnatprod.5b00947","article-title":"Feeling Nature\u2019s PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS)","volume":"79","author":"Baell","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1021\/acschembio.7b00903","article-title":"Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations","volume":"13","author":"Baell","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_62","unstructured":"Zhao, H., and Caflisch, A. (2014). Molecular dynamics in drug design. Eur. J. Med. Chem., 1\u201311."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.drudis.2015.01.003","article-title":"The impact of molecular dynamics on drug design: Applications for the characterization of ligand\u2013macromolecule complexes","volume":"20","author":"Mortier","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of Molecular Dynamics and Related Methods in Drug Discovery","volume":"59","author":"Masetti","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/01621459.1951.10500769","article-title":"The Kolmogorov-Smirnov Test for Goodness of Fit","volume":"46","author":"Massey","year":"1951","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1038\/s41598-018-35835-0","article-title":"Modulation of Human Hsp90\u03b1 Conformational Dynamics by Allosteric Ligand Interaction at the C-Terminal Domain","volume":"9","author":"Penkler","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev.biophys.36.040306.132550","article-title":"Calculation of Protein-Ligand Binding Affinities","volume":"36","author":"Gilson","year":"2007","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1021\/acs.jcim.7b00564","article-title":"Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations","volume":"57","author":"Cournia","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1146\/annurev-biophys-083012-130318","article-title":"Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design","volume":"42","author":"Chodera","year":"2013","journal-title":"Annu. Rev. Biophys."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/wcms.1157","article-title":"Frontiers in free-energy calculations of biological systems","volume":"4","author":"Chipot","year":"2014","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa-A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1093\/bioinformatics\/btx349","article-title":"MD-TASK: A software suite for analyzing molecular dynamics trajectories","volume":"33","author":"Brown","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1021\/acs.jcim.7b00630","article-title":"Allosteric Modulation of Human Hsp90\u03b1 Conformational Dynamics","volume":"58","author":"Penkler","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2006.0019","DOI":"10.1038\/msb4100063","article-title":"Residues crucial for maintaining short paths in network communication mediate signaling in proteins","volume":"2","author":"Fujihashi","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez Alvarez, L., Barreto Gomes, D.E., Hern\u00e1ndez Gonz\u00e1lez, J.E., and Pascutti, P.G. (2019). Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211227"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Novinec, M. (2017). Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182387"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1016\/j.bmc.2013.04.047","article-title":"Falcipain-2 inhibition by suramin and suramin analogues","volume":"21","author":"Marques","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3109\/14756366.2014.920839","article-title":"Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum","volume":"30","author":"Bertoldo","year":"2015","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0022-2836(77)80200-3","article-title":"The Protein Data Bank: A computer-based archival file for macromolecular structures","volume":"112","author":"Bernstein","year":"1977","journal-title":"J. Mol. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/med.20163","article-title":"Falcipain-2 inhibitors","volume":"30","author":"Ettari","year":"2010","journal-title":"Med. Res. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3636","DOI":"10.1016\/j.bmc.2016.06.003","article-title":"Bistacrine derivatives as new potent antimalarials","volume":"24","author":"Schmidt","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/j.bmcl.2014.01.062","article-title":"Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of \u03b1-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum","volume":"24","author":"Weldon","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"n\/a","DOI":"10.1002\/cmdc.201402079","article-title":"Synthesis and Biological Evaluation of Papain-Family Cathepsin\u2005L-Like Cysteine Protease Inhibitors Containing a 1,4-Benzodiazepine Scaffold as Antiprotozoal Agents","volume":"9","author":"Ettari","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"10557","DOI":"10.1021\/jm501439w","article-title":"Synthesis of Gallinamide A Analogues as Potent Falcipain Inhibitors and Antimalarials","volume":"57","author":"Conroy","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.bmcl.2011.12.011","article-title":"Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent","volume":"22","author":"Huang","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_88","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_89","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1021\/ar9500675","article-title":"Advances and Continuing Challenges in Achieving Realistic and Predictive Simulations of the Properties of Organic and Biological Molecules","volume":"29","author":"Models","year":"1996","journal-title":"Acc. Chem. Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sousa da Silva, A.W., and Vranken, W.F. (2012). ACPYPE-AnteChamber PYthon Parser interfacE. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-367"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3668","DOI":"10.1063\/1.470043","article-title":"Accuracy and efficiency of the particle mesh Ewald method","volume":"103","author":"Petersen","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s40265-018-0911-9","article-title":"Drugs in Development for Malaria","volume":"78","author":"Ashley","year":"2018","journal-title":"Drugs"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cell.2013.03.034","article-title":"Allostery in Disease and in Drug Discovery","volume":"153","author":"Nussinov","year":"2013","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Liu, J., and Nussinov, R. (2016). Allostery: An Overview of Its History, Concepts, Methods, and Applications. PLOS Comput. Biol., 12.","DOI":"10.1371\/journal.pcbi.1004966"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1002\/med.21317","article-title":"Harnessing Allostery: A Novel Approach to Drug Discovery","volume":"34","author":"Lu","year":"2014","journal-title":"Med. Res. Rev."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/22\/4036\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:32:39Z","timestamp":1760189559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/22\/4036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,7]]},"references-count":98,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["molecules24224036"],"URL":"https:\/\/doi.org\/10.3390\/molecules24224036","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,7]]}}}