{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T06:54:48Z","timestamp":1768805688803,"version":"3.49.0"},"reference-count":121,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Targeting <jats:italic>Plasmodium falciparum<\/jats:italic> (Pf) aminoacyl tRNA synthetases is a viable strategy to overcome malaria parasite multi-drug resistance. Here, we focused on <jats:italic>Pf<\/jats:italic> Isoleucyl tRNA synthetase (PfIleRS) to identify potential allosteric inhibitors from 1019 South African Natural Compounds (SANC). Eleven potential hits, which passed ADMET and PAINS, were selected based on their docking binding affinity which was higher for PfIleRS than for human IleRS. Molecular dynamics simulations revealed that the compounds, particularly SANC456, commonly induced considerable changes in the global conformation and dynamics of PfIleRS, suggesting potential allosteric modulatory effects. Importantly, all 11 SANC hits reduced the binding affinity of the nucleotide AMP molecule by at least 25%. Some SANC ligand-bound systems (SANC456, SANC1095, and SANC1104) significantly increased the distance between the AMP and Ile ligands. Possible explanations for these changes were explored using three dynamic residue network centrality metrics. <jats:italic>Betweenness centrality<\/jats:italic> identified a major allosteric pathway in holo PfIleRS spanning the entire protein length. In contrast, SANC382, SANC456, SANC522, SANC806 and SANC1095 ligand-bound systems exhibited delta <jats:italic>BC<\/jats:italic> pathways (SANC-protein minus holo-protein), induced by the ligands, extending from their respective pockets into the active site. Additionally, <jats:italic>eigenvector centrality<\/jats:italic> revealed two important residue clusters either side of the holo active site which became altered in the ligand-bound systems, indicating possible allosteric activity. Lastly, many SANC systems showed decreased <jats:italic>closeness centrality<\/jats:italic> of zinc finger and active site residues, including the HYGH and KMSKR motifs. We believe that the compounds identified in this study as potential allosteric inhibitors have strong translational potential and warrant further investigation through <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> experiments. Overall, they hold promise as starting points for the development of new and effective antimalarial therapies, particularly against multidrug-resistant Plasmodium parasites.<\/jats:p>","DOI":"10.1371\/journal.pone.0321444","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T18:04:58Z","timestamp":1747245898000},"page":"e0321444","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Allosteric modulation of Plasmodium falciparum Isoleucyl tRNA synthetase by South African natural compounds"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-5128","authenticated-orcid":true,"given":"Curtis","family":"Chepsiror","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayde","family":"Veldman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fisayo","family":"Olotu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6861-7849","authenticated-orcid":true,"given":"\u00d6zlem","family":"Tastan Bishop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"pone.0321444.ref001","volume-title":"World health statistics 2015","author":"World Health Organization","year":"2015"},{"issue":"3","key":"pone.0321444.ref002","doi-asserted-by":"crossref","first-page":"102860","DOI":"10.1016\/j.jbc.2022.102860","article-title":"Exploration of aminoacyl-tRNA synthetases from eukaryotic parasites for drug development","volume":"299","author":"J Gill","year":"2023","journal-title":"J Biol Chem"},{"key":"pone.0321444.ref003","volume-title":"Monitoring health for the sdgs, sustainable development goals","author":"World Health Statistics","year":"2023"},{"issue":"2","key":"pone.0321444.ref004","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s40471-021-00266-5","article-title":"Antimalarial Drug Resistance and Implications for the WHO Global Technical Strategy","volume":"8","author":"MM Ippolito","year":"2021","journal-title":"Curr Epidemiol Rep"},{"issue":"1","key":"pone.0321444.ref005","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2165\/00002018-200427010-00003","article-title":"Antimalarial drug toxicity: a review","volume":"27","author":"WRJ Taylor","year":"2004","journal-title":"Drug Saf"},{"issue":"1","key":"pone.0321444.ref006","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12936-019-2665-6","article-title":"Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study","volume":"18","author":"DW Nyamai","year":"2019","journal-title":"Malar J"},{"key":"pone.0321444.ref007","doi-asserted-by":"crossref","first-page":"100548","DOI":"10.1016\/j.ijpddr.2024.100548","article-title":"Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin","volume":"25","author":"F Olotu","year":"2024","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"686","key":"pone.0321444.ref008","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adc9249","article-title":"Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target","volume":"15","author":"ES Istvan","year":"2023","journal-title":"Sci Transl Med"},{"key":"pone.0321444.ref009","doi-asserted-by":"crossref","first-page":"5647","DOI":"10.1016\/j.csbj.2021.10.011","article-title":"Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance","volume":"19","author":"CJ Okeke","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"issue":"17","key":"pone.0321444.ref010","doi-asserted-by":"crossref","first-page":"167610","DOI":"10.1016\/j.jmb.2022.167610","article-title":"Allostery and Missense Mutations as Intermittently Linked Promising Aspects of Modern Computational Drug Discovery","volume":"434","author":"\u00d6 Tastan Bishop","year":"2022","journal-title":"J Mol Biol"},{"issue":"11","key":"pone.0321444.ref011","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.3390\/ijms21113803","article-title":"Identification of Selective Novel Hits against Plasmodium falciparum Prolyl tRNA Synthetase Active Site and a Predicted Allosteric Site Using in silico Approaches","volume":"21","author":"DW Nyamai","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0321444.ref012","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd2760","article-title":"Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders","volume":"8","author":"PJ Conn","year":"2009","journal-title":"Nat Rev Drug Discov"},{"issue":"5","key":"pone.0321444.ref013","first-page":"587","article-title":"Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs","volume":"13","author":"GJ Digby","year":"2010","journal-title":"Curr Opin Drug Discov Devel"},{"issue":"2","key":"pone.0321444.ref014","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1124\/pr.108.000992","article-title":"Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery","volume":"62","author":"T Kenakin","year":"2010","journal-title":"Pharmacol Rev"},{"issue":"3","key":"pone.0321444.ref015","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: advances and opportunities","volume":"20","author":"International Natural Product Sciences Taskforce","year":"2021","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0321444.ref016","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/B978-008045382-8.00679-1","article-title":"Bisubstrate Analog Inhibitors","volume-title":"Comprehensive Natural Products II","author":"PA Frantom","year":"2010"},{"issue":"5","key":"pone.0321444.ref017","first-page":"425","article-title":"Mupirocin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use","volume":"32","author":"A Ward","year":"1986","journal-title":"Drugs"},{"issue":"4","key":"pone.0321444.ref018","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":"ES Istvan","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0321444.ref019","first-page":"83","article-title":"The Chemistry of Thienopyrimidines","volume-title":"Advances in Heterocyclic Chemistry","author":"VP Litvinov","year":"2006"},{"issue":"1","key":"pone.0321444.ref020","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1038\/s41467-021-21902-0","article-title":"Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase","volume":"12","author":"B Chen","year":"2021","journal-title":"Nat Commun"},{"issue":"9","key":"pone.0321444.ref021","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1261\/rna.044404.114","article-title":"A bridge between the aminoacylation and editing domains of leucyl-tRNA synthetase is crucial for its synthetic activity","volume":"20","author":"Q Huang","year":"2014","journal-title":"RNA"},{"issue":"5","key":"pone.0321444.ref022","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1006\/jmbi.1999.3339","article-title":"Crystal structure of Escherichia coli methionyl-tRNA synthetase highlights species-specific features","volume":"294","author":"Y Mechulam","year":"1999","journal-title":"J Mol Biol"},{"key":"pone.0321444.ref023","first-page":"155","article-title":"Fidelity Mechanisms of the Aminoacyl-tRNA Synthetases.","volume-title":"Nucleic Acids and Molecular Biology","author":"AP Mascarenhas","year":"2009"},{"issue":"8","key":"pone.0321444.ref024","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1261\/rna.071720.119","article-title":"Aminoacyl-tRNA synthetases","volume":"26","author":"MA Rubio Gomez","year":"2020","journal-title":"RNA"},{"issue":"1","key":"pone.0321444.ref025","doi-asserted-by":"crossref","first-page":"5498","DOI":"10.1038\/s41467-023-41244-3","article-title":"Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif","volume":"14","author":"A Brkic","year":"2023","journal-title":"Nat Commun"},{"key":"pone.0321444.ref026","first-page":"103","article-title":"Coding of Class I and II Aminoacyl-tRNA Synthetases.","volume-title":"Advances in Experimental Medicine and Biology","author":"CW. Carter","year":"2017"},{"issue":"1","key":"pone.0321444.ref027","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpddr.2013.10.001","article-title":"Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites","volume":"4","author":"JS Pham","year":"2013","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"4","key":"pone.0321444.ref028","first-page":"350","article-title":"Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase","volume":"43","author":"S Chung","year":"2020","journal-title":"Mol Cells"},{"key":"pone.0321444.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gku316","article-title":"Deciphering key features in protein structures with the new ENDscript server","volume":"42","author":"X Robert","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0321444.ref030","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13321-021-00514-2","article-title":"SANCDB: an update on South African natural compounds and their readily available analogs","volume":"13","author":"BN Diallo","year":"2021","journal-title":"J Cheminform"},{"key":"pone.0321444.ref031","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":"R Hatherley","year":"2015","journal-title":"J Cheminform"},{"key":"pone.0321444.ref032","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: the Universal Protein Knowledgebase in 2023","volume":"51","author":"Consortium UniProt","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"pone.0321444.ref033","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0166698","article-title":"PRIMO: An Interactive Homology Modeling Pipeline","volume":"11","author":"R Hatherley","year":"2016","journal-title":"PLoS One"},{"key":"pone.0321444.ref034","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gki408","article-title":"The HHpred interactive server for protein homology detection and structure prediction","volume":"33","author":"J S\u00f6ding","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"pone.0321444.ref035","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/978-1-62703-646-7_17","article-title":"PROMALS3D: multiple protein sequence alignment enhanced with evolutionary and three-dimensional structural information","author":"J Pei","year":"2014","journal-title":"Methods Mol Biol"},{"key":"pone.0321444.ref036","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/978-1-0716-1036-7_13","article-title":"Alignment of Biological Sequences with Jalview","author":"JB Procter","year":"2021","journal-title":"Methods Mol Biol"},{"key":"pone.0321444.ref037","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S0076-6879(03)74020-8","article-title":"Modeller: generation and refinement of homology-based protein structure models","volume":"374","author":"A Fiser","year":"2003","journal-title":"Methods Enzymol"},{"key":"pone.0321444.ref038","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkp322","article-title":"QMEAN server for protein model quality estimation","volume":"37","author":"P Benkert","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"pone.0321444.ref039","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"M Wiederstein","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"pone.0321444.ref040","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0076-6879(97)77022-8","article-title":"VERIFY3D: assessment of protein models with three-dimensional profiles","volume":"277","author":"D Eisenberg","year":"1997","journal-title":"Methods Enzymol"},{"issue":"2","key":"pone.0321444.ref041","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1021\/ci800324m","article-title":"Identifying and characterizing binding sites and assessing druggability","volume":"49","author":"TA Halgren","year":"2009","journal-title":"J Chem Inf Model"},{"issue":"15","key":"pone.0321444.ref042","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1093\/bioinformatics\/bts310","article-title":"DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment","volume":"28","author":"A Volkamer","year":"2012","journal-title":"Bioinformatics"},{"key":"pone.0321444.ref043","article-title":"FTMAP: extended protein mapping with user-selected probe molecules","volume":"40","author":"CH Ngan","year":"2012","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0321444.ref044","doi-asserted-by":"crossref","first-page":"035015","DOI":"10.1088\/2632-2153\/abe6d6","article-title":"PASSer: Prediction of Allosteric Sites Server","volume":"2","author":"H Tian","year":"2021","journal-title":"Mach Learn Sci Technol"},{"key":"pone.0321444.ref045","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkw408","article-title":"ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules","volume":"44","author":"H Ashkenazy","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"9","key":"pone.0321444.ref046","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1093\/molbev\/msh194","article-title":"Comparison of site-specific rate-inference methods for protein sequences: empirical Bayesian methods are superior","volume":"21","author":"I Mayrose","year":"2004","journal-title":"Mol Biol Evol"},{"issue":"1","key":"pone.0321444.ref047","first-page":"85","article-title":"Investigating the Impact of Min-Max Data Normalization on the Regression Performance of K-Nearest Neighbor with Different Similarity Measurements","volume":"10","author":"PJ Muhammad Ali","year":"2022","journal-title":"ARO Sci J KOYA Univ"},{"key":"pone.0321444.ref048","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkm276","article-title":"PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations","volume":"35","author":"TJ Dolinsky","year":"2007","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pone.0321444.ref049","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0177923","article-title":"Fully automated antibody structure prediction using BIOVIA tools: Validation study","volume":"12","author":"H Kemmish","year":"2017","journal-title":"PLoS One"},{"issue":"19","key":"pone.0321444.ref050","doi-asserted-by":"crossref","first-page":"3836","DOI":"10.1093\/bioinformatics\/btz152","article-title":"AutoDock Bias: improving binding mode prediction and virtual screening using known protein-ligand interactions","volume":"35","author":"JP Arcon","year":"2019","journal-title":"Bioinformatics"},{"issue":"2","key":"pone.0321444.ref051","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":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"issue":"13","key":"pone.0321444.ref052","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"12","key":"pone.0321444.ref053","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.3390\/biom12121764","article-title":"Boosting the Full Potential of PyMOL with Structural Biology Plugins","volume":"12","author":"S Rosignoli","year":"2022","journal-title":"Biomolecules"},{"issue":"2","key":"pone.0321444.ref054","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/protein\/8.2.127","article-title":"LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions","volume":"8","author":"AC Wallace","year":"1995","journal-title":"Protein Eng"},{"issue":"14","key":"pone.0321444.ref055","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":"MM Mysinger","year":"2012","journal-title":"J Med Chem"},{"issue":"12","key":"pone.0321444.ref056","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1021\/acs.jcim.6b00283","article-title":"Screening Explorer-An Interactive Tool for the Analysis of Screening Results","volume":"56","author":"C Empereur-Mot","year":"2016","journal-title":"J Chem Inf Model"},{"issue":"19","key":"pone.0321444.ref057","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1002\/jcc.25187","article-title":"Fast and flexible gpu accelerated binding free energy calculations within the amber molecular dynamics package","volume":"39","author":"DJ Mermelstein","year":"2018","journal-title":"J Comput Chem"},{"issue":"9","key":"pone.0321444.ref058","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"J Wang","year":"2004","journal-title":"J Comput Chem"},{"key":"pone.0321444.ref059","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/1756-0500-5-367","article-title":"ACPYPE - AnteChamber PYthon Parser interfacE","volume":"5","author":"AW Sousa da Silva","year":"2012","journal-title":"BMC Res Notes"},{"issue":"16","key":"pone.0321444.ref060","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"DA Case","year":"2005","journal-title":"J Comput Chem"},{"issue":"25","key":"pone.0321444.ref061","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1002\/jcc.25382","article-title":"Parallelization of CPPTRAJ enables large scale analysis of molecular dynamics trajectory data","volume":"39","author":"DR Roe","year":"2018","journal-title":"J Comput Chem"},{"issue":"10","key":"pone.0321444.ref062","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1021\/ci4002475","article-title":"MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions","volume":"53","author":"M Ylilauri","year":"2013","journal-title":"J Chem Inf Model"},{"issue":"17","key":"pone.0321444.ref063","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":"DK Brown","year":"2017","journal-title":"Bioinformatics"},{"key":"pone.0321444.ref064","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.1016\/j.csbj.2021.08.043","article-title":"MDM-TASK-web: MD-TASK and MODE-TASK web server for analyzing protein dynamics","volume":"19","author":"O Sheik Amamuddy","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"issue":"4","key":"pone.0321444.ref065","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1021\/acs.jctc.8b01197","article-title":"Robust Determination of Protein Allosteric Signaling Pathways","volume":"15","author":"WM Botello-Smith","year":"2019","journal-title":"J Chem Theory Comput"},{"issue":"52","key":"pone.0321444.ref066","article-title":"Eigenvector centrality for characterization of protein allosteric pathways","volume":"115","author":"CFA Negre","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"pone.0321444.ref067","doi-asserted-by":"crossref","first-page":"102774","DOI":"10.1016\/j.sbi.2024.102774","article-title":"Machine learning approaches in predicting allosteric sites","volume":"85","author":"F Ner\u00edn-Fonz","year":"2024","journal-title":"Curr Opin Struct Biol"},{"issue":"60","key":"pone.0321444.ref068","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: statistical data visualization","volume":"6","author":"M Waskom","year":"2021","journal-title":"JOSS"},{"issue":"7","key":"pone.0321444.ref069","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0021812","article-title":"Computational reverse-engineering of a spider-venom derived peptide active against Plasmodium falciparum SUB1","volume":"6","author":"G Bastianelli","year":"2011","journal-title":"PLoS One"},{"issue":"1","key":"pone.0321444.ref070","article-title":"Identifying druggable targets by protein microenvironments matching: application to transcription factors","volume":"3","author":"T Liu","year":"2014","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"pone.0321444.ref071","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3389\/fchem.2020.00443","article-title":"In silico Druggability Assessment of the NUDIX Hydrolase Protein Family as a Workflow for Target Prioritization","volume":"8","author":"M Michel","year":"2020","journal-title":"Front Chem"},{"issue":"1","key":"pone.0321444.ref072","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2174\/156802610790232233","article-title":"Hydrophobicity--shake flasks, protein folding and drug discovery","volume":"10","author":"A Sarkar","year":"2010","journal-title":"Curr Top Med Chem"},{"key":"pone.0321444.ref073","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.3762\/bjoc.18.141","article-title":"On drug discovery against infectious diseases and academic medicinal chemistry contributions","volume":"18","author":"YL Janin","year":"2022","journal-title":"Beilstein J Org Chem"},{"issue":"1","key":"pone.0321444.ref074","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1124\/pr.112.007336","article-title":"Computational methods in drug discovery","volume":"66","author":"G Sliwoski","year":"2013","journal-title":"Pharmacol Rev"},{"key":"pone.0321444.ref075","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/B978-0-12-802225-2.00006-4","article-title":"Small Molecules","volume-title":"In Situ Tissue Regeneration","author":"B Lu","year":"2016"},{"issue":"7","key":"pone.0321444.ref076","article-title":"Rational engineering of enzyme allosteric regulation through sequence evolution analysis","volume":"8","author":"J-S Yang","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"pone.0321444.ref077","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":"Y Westermaier","year":"2015","journal-title":"Methods"},{"issue":"10","key":"pone.0321444.ref078","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":"G Mugumbate","year":"2013","journal-title":"J Comput Aided Mol Des"},{"issue":"22","key":"pone.0321444.ref079","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.3390\/molecules24224036","article-title":"South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches","volume":"24","author":"T Musyoka","year":"2019","journal-title":"Molecules"},{"issue":"8","key":"pone.0321444.ref080","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3390\/ph16081124","article-title":"Identification of Drug Targets and Their Inhibitors in Yersinia pestis Strain 91001 through Subtractive Genomics, Machine Learning, and MD Simulation Approaches","volume":"16","author":"H Ali","year":"2023","journal-title":"Pharmaceuticals (Basel)"},{"issue":"1","key":"pone.0321444.ref081","doi-asserted-by":"crossref","first-page":"188","DOI":"10.3390\/molecules24010188","article-title":"Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis","volume":"24","author":"A Amusengeri","year":"2019","journal-title":"Molecules"},{"issue":"22","key":"pone.0321444.ref082","doi-asserted-by":"crossref","first-page":"5574","DOI":"10.3390\/ijms20225574","article-title":"Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s","volume":"20","author":"A Amusengeri","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0321444.ref083","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.3390\/ijms22042138","article-title":"Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane","volume":"22","author":"L Chebon-Bore","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"24","key":"pone.0321444.ref084","doi-asserted-by":"crossref","DOI":"10.1002\/slct.202300277","article-title":"Discovery of Potential KRAS\u2010SOS1 Inhibitors from South African Natural Compounds: An In silico Approach","volume":"8","author":"AR Issahaku","year":"2023","journal-title":"ChemistrySelect"},{"issue":"10","key":"pone.0321444.ref085","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1080\/07391102.2020.1856186","article-title":"Inhibition analysis of aflatoxin by in silico targeting the thioesterase domain of polyketide synthase enzyme in Aspergillus ssp","volume":"40","author":"MM Labib","year":"2022","journal-title":"J Biomol Struct Dyn"},{"key":"pone.0321444.ref086","doi-asserted-by":"crossref","first-page":"23690","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":"TM Musyoka","year":"2016","journal-title":"Sci Rep"},{"issue":"10","key":"pone.0321444.ref087","first-page":"1957","article-title":"Natural Perylenequinone Compounds as Potent Inhibitors of Schistosoma mansoni Glutathione S-Transferase","volume":"13","author":"B Otarigho","year":"2023","journal-title":"Life (Basel)"},{"issue":"1","key":"pone.0321444.ref088","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":"DL Penkler","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0321444.ref089","doi-asserted-by":"crossref","first-page":"6431","DOI":"10.1016\/j.csbj.2021.11.016","article-title":"Novel dynamic residue network analysis approaches to study allosteric modulation: SARS-CoV-2 Mpro and its evolutionary mutations as a case study","volume":"19","author":"O Sheik Amamuddy","year":"2021","journal-title":"Computational and Structural Biotechnology Journal"},{"issue":"9","key":"pone.0321444.ref090","doi-asserted-by":"crossref","first-page":"554","DOI":"10.3390\/md20090554","article-title":"Targeted Isolation of Antibiotic Brominated Alkaloids from the Marine Sponge Pseudoceratina durissima Using Virtual Screening and Molecular Networking","volume":"20","author":"J Lever","year":"2022","journal-title":"Mar Drugs"},{"issue":"8","key":"pone.0321444.ref091","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3390\/md17080439","article-title":"New Discorhabdin Alkaloids from the Antarctic Deep-Sea Sponge Latrunculia biformis","volume":"17","author":"F Li","year":"2019","journal-title":"Mar Drugs"},{"key":"pone.0321444.ref092","first-page":"2803063","article-title":"In Vitro Antibacterial Activities of Methanolic Extracts of Fruits, Seeds, and Bark of Zanthoxylum armatum DC","author":"N Phuyal","year":"2020","journal-title":"J Trop Med"},{"issue":"1","key":"pone.0321444.ref093","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/BF02136759","article-title":"Crotsparine, a new proaporphine alkaloid from Croton sparsiflorus Morong","volume":"24","author":"DS Bhakuni","year":"1968","journal-title":"Experientia"},{"issue":"2","key":"pone.0321444.ref094","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1055\/s-2002-20245","article-title":"Antiplasmodial activity of Uvaria klaineana","volume":"68","author":"B Akendengue","year":"2002","journal-title":"Planta Med"},{"issue":"20","key":"pone.0321444.ref095","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1016\/j.phytochem.2007.05.022","article-title":"An appetite suppressant from Hoodia species","volume":"68","author":"FR van Heerden","year":"2007","journal-title":"Phytochemistry"},{"issue":"2","key":"pone.0321444.ref096","doi-asserted-by":"crossref","first-page":"150","DOI":"10.5941\/MYCO.2015.43.2.150","article-title":"In Vitro Antifungal Activity and Mode of Action of 2\u2019,4\u2019-Dihydroxychalcone against Aspergillus fumigatus","volume":"43","author":"YH Seo","year":"2015","journal-title":"Mycobiology"},{"issue":"9","key":"pone.0321444.ref097","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1128\/AAC.48.9.3241-3245.2004","article-title":"Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium falciparum-infected erythrocytes","volume":"48","author":"M-L Go","year":"2004","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0321444.ref098","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.forsciint.2012.04.008","article-title":"(1S,2S)-1-Methylamino-1-phenyl-2-chloropropane: Route specific marker impurity of methamphetamine synthesized from ephedrine via chloroephedrine","volume":"221","author":"BJ Ko","year":"2012","journal-title":"Forensic Sci Int"},{"issue":"4","key":"pone.0321444.ref099","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.neuro.2006.01.012","article-title":"Increase of glutamate\/N-methyl-D-aspartate receptor immunodensity in the dentate gyrus of rats following pseudoephedrine administration","volume":"27","author":"S Nudmamud-Thanoi","year":"2006","journal-title":"Neurotoxicology"},{"issue":"4","key":"pone.0321444.ref100","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.3390\/molecules15042398","article-title":"Pellitorine, a potential anti-cancer lead compound against HL6 and MCT-7 cell lines and microbial transformation of piperine from Piper Nigrum","volume":"15","author":"GCL Ee","year":"2010","journal-title":"Molecules"},{"issue":"1","key":"pone.0321444.ref101","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1007\/s11686-024-00792-4","article-title":"Exploring the Efficacy of Pellitorine as an Antiparasitic Agent Against Argulus: Impacts on Antioxidant Levels and Immune Responses in Goldfish (Carassius auratus)","volume":"69","author":"S Boopathi","year":"2024","journal-title":"Acta Parasitol"},{"issue":"2","key":"pone.0321444.ref102","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1007\/s00344-020-10127-y","article-title":"Production Enhancement of Medicinally Active Coumarin and Phenolic Compounds in Hairy Root Cultures of Pelargonium sidoides: The Effect of Elicitation and Sucrose","volume":"40","author":"Z Yousefian","year":"2020","journal-title":"J Plant Growth Regul"},{"issue":"3","key":"pone.0321444.ref103","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0367-326X(02)00070-9","article-title":"Arteminin, a new coumarin from Artemisia apiacea","volume":"73","author":"KS Kim","year":"2002","journal-title":"Fitoterapia"},{"issue":"1","key":"pone.0321444.ref104","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13071-023-05755-8","article-title":"Malaria therapeutics: are we close enough?","volume":"16","author":"H Tripathi","year":"2023","journal-title":"Parasit Vectors"},{"issue":"3","key":"pone.0321444.ref105","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.taap.2005.07.011","article-title":"The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress","volume":"212","author":"C Riganti","year":"2006","journal-title":"Toxicol Appl Pharmacol"},{"issue":"3","key":"pone.0321444.ref106","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.4067\/s0717-97072020000204934","article-title":"Synthesis and crystal structure analysis of a new chalcone derivative of apocynin","volume":"65","author":"M Z\u00e1rraga","year":"2020","journal-title":"J Chil Chem Soc"},{"key":"pone.0321444.ref107","doi-asserted-by":"crossref","first-page":"106803","DOI":"10.1016\/j.intimp.2020.106803","article-title":"Sesquiterpene lactone Zaluzanin D alters MMP-9 promoter methylation in differentiated THP-1 monocytic cells and down regulates inflammatory cytokines IL-1\u03b2 and TNF-\u03b1","volume":"87","author":"V Cheeran","year":"2020","journal-title":"Int Immunopharmacol"},{"issue":"5","key":"pone.0321444.ref108","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0367-326X(03)00054-6","article-title":"Zaluzanin D: a fungistatic sesquiterpene from Vernonia arborea","volume":"74","author":"GN Krishna Kumari","year":"2003","journal-title":"Fitoterapia"},{"issue":"1","key":"pone.0321444.ref109","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13321-020-00437-4","article-title":"Aromatic clusters in protein-protein and protein-drug complexes","volume":"12","author":"E Lanzarotti","year":"2020","journal-title":"J Cheminform"},{"issue":"6","key":"pone.0321444.ref110","doi-asserted-by":"crossref","first-page":"5634","DOI":"10.1021\/acsomega.2c07111","article-title":"Complexity of the Role of Various Site-Specific and Selective Sudlow Binding Site Drugs in the Energetics and Stability of the Acridinedione Dye-Bovine Serum Albumin Complex: A Molecular Docking Approach","volume":"8","author":"SM Vinod","year":"2023","journal-title":"ACS Omega"},{"key":"pone.0321444.ref111","doi-asserted-by":"crossref","first-page":"107705","DOI":"10.1016\/j.biotechadv.2021.107705","article-title":"Structure-function relationships in NDP-sugar active SDR enzymes: Fingerprints for functional annotation and enzyme engineering","volume":"48","author":"M Da Costa","year":"2021","journal-title":"Biotechnol Adv"},{"issue":"5","key":"pone.0321444.ref112","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1021\/bi00405a028","article-title":"Reconstruction by site-directed mutagenesis of the transition state for the activation of tyrosine by the tyrosyl-tRNA synthetase: a mobile loop envelopes the transition state in an induced-fit mechanism","volume":"27","author":"AR Fersht","year":"1988","journal-title":"Biochemistry"},{"issue":"3","key":"pone.0321444.ref113","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0022-2836(91)90750-Z","article-title":"Lysine 335, part of the KMSKS signature sequence, plays a crucial role in the amino acid activation catalysed by the methionyl-tRNA synthetase from Escherichia coli","volume":"217","author":"Y Mechulam","year":"1991","journal-title":"J Mol Biol"},{"issue":"4","key":"pone.0321444.ref114","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1006\/jmbi.1994.1601","article-title":"Methionyl-tRNA synthetase needs an intact and mobile 332KMSKS336 motif in catalysis of methionyl adenylate formation","volume":"242","author":"E Schmitt","year":"1994","journal-title":"J Mol Biol"},{"issue":"25","key":"pone.0321444.ref115","doi-asserted-by":"crossref","first-page":"10709","DOI":"10.1074\/jbc.M116.770826","article-title":"Acetylation of lysine \u220a-amino groups regulates aminoacyl-tRNA synthetase activity in Escherichia coli","volume":"292","author":"Q Ye","year":"2017","journal-title":"J Biol Chem"},{"issue":"6","key":"pone.0321444.ref116","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.sbi.2009.09.004","article-title":"Adenylate-forming enzymes","volume":"19","author":"S Schmelz","year":"2009","journal-title":"Curr Opin Struct Biol"},{"key":"pone.0321444.ref117","doi-asserted-by":"crossref","first-page":"4562","DOI":"10.1016\/j.csbj.2022.08.015","article-title":"Evolutionary progression of collective mutations in Omicron sub-lineages towards efficient RBD-hACE2: Allosteric communications between and within viral and human proteins","volume":"20","author":"V Barozi","year":"2022","journal-title":"Comput Struct Biotechnol J"},{"key":"pone.0321444.ref118","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1016\/j.csbj.2021.06.004","article-title":"Protein conformational switch discerned via network centrality properties","volume":"19","author":"D Foutch","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"issue":"4","key":"pone.0321444.ref119","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1021\/acs.chemrev.7b00305","article-title":"Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation","volume":"118","author":"H-X Zhou","year":"2018","journal-title":"Chem Rev"},{"issue":"3","key":"pone.0321444.ref120","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1093\/nar\/gkw1182","article-title":"The complex evolutionary history of aminoacyl-tRNA synthetases","volume":"45","author":"A Chaliotis","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"6289","key":"pone.0321444.ref121","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/347203a0","article-title":"Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs","volume":"347","author":"G Eriani","year":"1990","journal-title":"Nature"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0321444","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T18:05:20Z","timestamp":1747245920000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0321444"}},"subtitle":[],"editor":[{"given":"Opeyemi","family":"Iwaloye","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,5,14]]},"references-count":121,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0321444","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,14]]}}}