{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T01:07:23Z","timestamp":1776906443268,"version":"3.51.2"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"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>Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and their activation has been proven to treat mild liver fibrosis, reduce steatosis, inflammation, and the extrahepatic effects of chronic liver disease. Considering the significance of the PPARs, it is targeted for the treatment of Non-Alcoholic Steatohepatitis (NASH), for which currently there is no FDA-approved drug. Lanifibranor is a next-generation highly potential indole sulfonamide derivative that is presently in clinical trial phase III as an anti-NASH drug which fully activates PPAR\u03b1 and PPAR\u03b4 and partially activates PPAR\u03b3. In the current study, a comprehensive computational investigation including 3D-QSAR pharmacophore modeling, MD simulations and binding free energy calculations is performed to get insights into the activation mechanism of the Lanifibranor. Furthermore, FDA-approved drugs were explored for repurposing through virtual screening against each PPAR pharmacophore to identify potential drug candidates. Forasartan, Raltitrexed, and Lifitegrast stood out as potential agonists for PPAR\u03b1 (full agonist), PPAR\u03b3 (partial agonist), and PPAR\u03b4 (full agonist), respectively. The findings of the study highlighted a lack of hydrogen bond acceptor feature in Raltitrexed and Lanifibranor which is responsible for partial activation of PPAR\u03b3 that plays a critical role in preventing lipid accumulation. In addition to this, the significant role of AF2 domain in full and partial activation of PPARs through electrostatic interactions was also revealed, that facilitates the anchoring of ligand within the binding cavity. Moreover, common chemical scaffolds (methyl sulfonyl benzene, butyric acid, and chlorobenzene) identified using Fingerprinting technique were presented in this study which hold the potential to aid in the design and development of target specific novel Pan PPAR medications in future.<\/jats:p>","DOI":"10.1371\/journal.pone.0283743","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T17:49:52Z","timestamp":1680284992000},"page":"e0283743","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Deciphering the relational dynamics of AF-2 domain of PAN PPAR through drug repurposing and comparative simulations"],"prefix":"10.1371","volume":"18","author":[{"given":"Fouzia","family":"Gul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nousheen","family":"Parvaiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5624-6120","authenticated-orcid":true,"given":"Syed Sikander","family":"Azam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"issue":"5","key":"pone.0283743.ref001","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1586\/egh.10.56","article-title":"Nonalcoholic steatohepatitis: risk factors and diagnosis","volume":"4","author":"LA Adams","year":"2010","journal-title":"Expert review of gastroenterology & hepatology"},{"issue":"3","key":"pone.0283743.ref002","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings","volume":"53","author":"EM Brunt","year":"2011","journal-title":"Hepatology"},{"issue":"9","key":"pone.0283743.ref003","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.humpath.2004.04.017","article-title":"Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens","volume":"35","author":"EM Brunt","year":"2004","journal-title":"Human pathology"},{"issue":"5","key":"pone.0283743.ref004","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.jhep.2005.02.007","article-title":"Late complications of NASH: a challenge for hepatologists","volume":"42","author":"E. Bugianesi","year":"2005","journal-title":"Journal of Hepatology"},{"key":"pone.0283743.ref005","first-page":"320","author":"E Vanni","year":"2010","journal-title":"From the metabolic syndrome to nAFld or vice versa"},{"issue":"9","key":"pone.0283743.ref006","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1111\/j.1572-0241.2003.07659.x","article-title":"The natural history of nonalcoholic fatty liver disease: a clinical histopathological study","volume":"98","author":"SA Harrison","year":"2003","journal-title":"The American journal of gastroenterology"},{"issue":"6","key":"pone.0283743.ref007","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity","volume":"116","author":"CA Matteoni","year":"1999","journal-title":"Gastroenterology"},{"key":"pone.0283743.ref008","article-title":"editors. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease","author":"J Ludwig","year":"1980","journal-title":"Mayo Clinic Proceedings"},{"issue":"1","key":"pone.0283743.ref009","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cld.2017.08.003","article-title":"The natural history of nonalcoholic fatty liver disease\u2014an evolving view","volume":"22","author":"CC Lindenmeyer","year":"2018","journal-title":"Clinics in liver disease"},{"issue":"4","key":"pone.0283743.ref010","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/hep.21327","article-title":"Long\u2010term follow\u2010up of patients with NAFLD and elevated liver enzymes","volume":"44","author":"M Ekstedt","year":"2006","journal-title":"Hepatology"},{"issue":"7","key":"pone.0283743.ref011","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1053\/jlts.2001.25453","article-title":"Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease","volume":"7","author":"M Charlton","year":"2001","journal-title":"Liver Transplantation"},{"issue":"6","key":"pone.0283743.ref012","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1089\/met.2015.1502","article-title":"A perspective on metabolic syndrome and nonalcoholic fatty liver disease","volume":"13","author":"G Targher","year":"2015","journal-title":"Metabolic Syndrome and Related Disorders"},{"issue":"3","key":"pone.0283743.ref013","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.dld.2014.09.020","article-title":"Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome","volume":"47","author":"A Lonardo","year":"2015","journal-title":"Digestive and Liver disease"},{"issue":"11","key":"pone.0283743.ref014","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1111\/hepr.12656","article-title":"The independent predictors of non\u2010alcoholic steatohepatitis and its individual histological features. Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment","volume":"46","author":"S Ballestri","year":"2016","journal-title":"Hepatology Research"},{"key":"pone.0283743.ref015","first-page":"S18885","article-title":"Nonalcoholic fatty liver disease: epidemiology, pathogenesis, natural history, diagnosis, and current treatment options","volume":"8","author":"BA Banini","year":"2016","journal-title":"Clinical Medicine Insights: Therapeutics"},{"issue":"9","key":"pone.0283743.ref016","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.3390\/ijms17091575","article-title":"Molecular Pathogenesis of NASH","volume":"17","author":"C Alessandra","year":"2016","journal-title":"International Journal of Molecular Sciences"},{"issue":"7","key":"pone.0283743.ref017","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"S. Friedman","year":"2018","journal-title":"Nat Med"},{"issue":"1","key":"pone.0283743.ref018","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1053\/gast.2001.25540","article-title":"Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese","volume":"121","author":"JB Dixon","year":"2001","journal-title":"Gastroenterology"},{"issue":"20","key":"pone.0283743.ref019","doi-asserted-by":"crossref","first-page":"827","DOI":"10.4254\/wjh.v8.i20.827","article-title":"Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management","volume":"8","author":"VVR Kanth","year":"2016","journal-title":"World journal of hepatology"},{"issue":"4","key":"pone.0283743.ref020","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s11739-011-0609-4","article-title":"Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?","volume":"8","author":"L Carulli","year":"2013","journal-title":"Internal and emergency medicine"},{"key":"pone.0283743.ref021","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/liv.14355","article-title":"Current management of non\u2010alcoholic steatohepatitis","volume":"40","author":"MD Muthiah","year":"2020","journal-title":"Liver International"},{"issue":"2","key":"pone.0283743.ref022","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41575-020-00406-0","article-title":"Nonalcoholic fatty liver disease: another leap forward","volume":"18","author":"MF Abdelmalek","year":"2021","journal-title":"Nature Reviews Gastroenterology & Hepatology"},{"issue":"4","key":"pone.0283743.ref023","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1002\/hep.27678","article-title":"Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases\u2013US Food and Drug Administration Joint Workshop","volume":"61","author":"AJ Sanyal","year":"2015","journal-title":"Hepatology"},{"issue":"12","key":"pone.0283743.ref024","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1080\/13543784.2020.1839888","article-title":"The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success","volume":"29","author":"JP Drenth","year":"2020","journal-title":"Expert Opinion on Investigational Drugs"},{"key":"pone.0283743.ref025","doi-asserted-by":"crossref","first-page":"154170","DOI":"10.1016\/j.metabol.2020.154170","article-title":"Complications, morbidity and mortality of nonalcoholic fatty liver disease","volume":"111","author":"A Mantovani","year":"2020","journal-title":"Metabolism"},{"issue":"2","key":"pone.0283743.ref026","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1080\/13543784.2020.1668926","article-title":"Multi-drug approaches to NASH: what\u2019s in the development pipeline?","volume":"29","author":"MP Johnston","year":"2020","journal-title":"Expert Opinion on Investigational Drugs"},{"issue":"1","key":"pone.0283743.ref027","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3748\/wjg.14.22","article-title":"Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease","volume":"14","author":"ER Kallwitz","year":"2008","journal-title":"World journal of gastroenterology: WJG"},{"issue":"1","key":"pone.0283743.ref028","first-page":"1","article-title":"PPARs modulate cardiac metabolism and mitochondrial function in diabetes","volume":"24","author":"T-W Lee","year":"2017","journal-title":"Journal of biomedical science"},{"issue":"4","key":"pone.0283743.ref029","doi-asserted-by":"crossref","first-page":"949","DOI":"10.3390\/ijms19040949","article-title":"Pivotal roles of peroxisome proliferator-activated receptors (PPARs) and their signal cascade for cellular and whole-body energy homeostasis","volume":"19","author":"S Lamichane","year":"2018","journal-title":"International journal of molecular sciences"},{"key":"pone.0283743.ref030","doi-asserted-by":"crossref","DOI":"10.1155\/2009\/818945","article-title":"Cross-talk between PPAR and insulin signaling and modulation of insulin sensitivity","volume":"2009","author":"A Leonardini","year":"2009","journal-title":"PPAR research"},{"key":"pone.0283743.ref031","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1021\/jm990554g","article-title":"The PPARs: from orphan receptors to drug discovery","volume":"43","author":"T. Willson","year":"2000","journal-title":"J Med Chem"},{"issue":"3","key":"pone.0283743.ref032","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular mechanism of PPAR\u03b1 action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease","volume":"62","author":"M Pawlak","year":"2015","journal-title":"Journal of hepatology"},{"issue":"9","key":"pone.0283743.ref033","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1023\/B:PHAM.0000041444.06122.8d","article-title":"Peroxisome proliferator-activated receptor (PPAR)-\u03b1: a pharmacological target with a promising future","volume":"21","author":"DH van Raalte","year":"2004","journal-title":"Pharmaceutical research"},{"issue":"9","key":"pone.0283743.ref034","doi-asserted-by":"crossref","first-page":"4318","DOI":"10.1073\/pnas.94.9.4318","article-title":"Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors \u03b1 and \u03b3","volume":"94","author":"SA Kliewer","year":"1997","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"36","key":"pone.0283743.ref035","doi-asserted-by":"crossref","first-page":"34268","DOI":"10.1074\/jbc.M300043200","article-title":"Liver peroxisome proliferator-activated receptor \u03b3 contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass","volume":"278","author":"O Gavrilova","year":"2003","journal-title":"Journal of Biological Chemistry"},{"issue":"26","key":"pone.0283743.ref036","doi-asserted-by":"crossref","first-page":"15924","DOI":"10.1073\/pnas.0306981100","article-title":"Activation of peroxisome proliferator-activated receptor \u03b4 induces fatty acid \u03b2-oxidation in skeletal muscle and attenuates metabolic syndrome","volume":"100","author":"T Tanaka","year":"2003","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"pone.0283743.ref037","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/toxsci\/kfp212","article-title":"Ligand Activation of Peroxisome Proliferator\u2013Activated Receptor-\u03b2\/\u03b4 and Inhibition of Cyclooxygenase-2 Enhances Inhibition of Skin Tumorigenesis","volume":"113","author":"MT Bility","year":"2010","journal-title":"Toxicological Sciences"},{"issue":"7","key":"pone.0283743.ref038","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/hep4.1072","article-title":"The selective peroxisome proliferator\u2013activated receptor\u2010delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice","volume":"1","author":"F Haczeyni","year":"2017","journal-title":"Hepatology communications"},{"issue":"6","key":"pone.0283743.ref039","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1111\/liv.13634","article-title":"Dual PPAR \u03b1\/\u03b3 agonist Saroglitazar improves liver histopathology and biochemistry in experimental NASH models","volume":"38","author":"MR Jain","year":"2018","journal-title":"Liver International"},{"key":"pone.0283743.ref040","doi-asserted-by":"crossref","DOI":"10.1155\/2012\/757803","article-title":"PPARs in liver diseases and cancer: epigenetic regulation by microRNAs","volume":"2012","author":"M Peyrou","year":"2012","journal-title":"PPAR research"},{"issue":"27","key":"pone.0283743.ref041","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.2174\/09298673113209990136","article-title":"Hepatic PPARs: their role in liver physiology, fibrosis and treatment","volume":"20","author":"E M Zardi","year":"2013","journal-title":"Current Medicinal Chemistry"},{"issue":"6","key":"pone.0283743.ref042","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1021\/acs.jmedchem.7b01285","article-title":"Design, synthesis, and evaluation of a novel series of indole sulfonamide peroxisome proliferator activated receptor (PPAR) \u03b1\/\u03b3\/\u03b4 triple activators: discovery of lanifibranor, a new antifibrotic clinical candidate","volume":"61","author":"B Boubia","year":"2018","journal-title":"Journal of medicinal chemistry"},{"issue":"6","key":"pone.0283743.ref043","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/hep4.1057","article-title":"The new\u2010generation pan\u2010peroxisome proliferator\u2010activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis","volume":"1","author":"G Wettstein","year":"2017","journal-title":"Hepatology communications"},{"key":"pone.0283743.ref044","unstructured":"BIOVIA DS. Discovery Studio; 19.1. 0.18287. Dassault Syst\u00e8mes: San Diego, CA, USA. 2019."},{"issue":"1","key":"pone.0283743.ref045","first-page":"1","article-title":"Structures of PPAR\u03b3 complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs","volume":"7","author":"MA Lee","year":"2017","journal-title":"Scientific reports"},{"issue":"13","key":"pone.0283743.ref046","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"Journal of computational chemistry"},{"issue":"2","key":"pone.0283743.ref047","first-page":"113","article-title":"High throughput docking for library design and library prioritization. Proteins: Structure, Function, and","volume":"43","author":"DJ Diller","year":"2001","journal-title":"Bioinformatics"},{"key":"pone.0283743.ref048","doi-asserted-by":"crossref","first-page":"107367","DOI":"10.1016\/j.compbiolchem.2020.107367","article-title":"Similar, or dissimilar, that is the question. How different are methods for comparison of compounds similarity?","volume":"88","author":"K Rajda","year":"2020","journal-title":"Computational Biology and Chemistry"},{"issue":"3","key":"pone.0283743.ref049","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/jcc.540020311","article-title":"AMBER: Assisted model building with energy refinement. A general program for modeling molecules and their interactions","volume":"2","author":"PK Weiner","year":"1981","journal-title":"Journal of Computational Chemistry"},{"issue":"6","key":"pone.0283743.ref050","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1080\/00268978800101881","article-title":"An analysis of the accuracy of Langevin and molecular dynamics algorithms","volume":"65","author":"RW Pastor","year":"1988","journal-title":"Molecular Physics"},{"issue":"5","key":"pone.0283743.ref051","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/1096-987X(20010415)22:5<501::AID-JCC1021>3.0.CO;2-V","article-title":"A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations","volume":"22","author":"V Kr\u00e4utler","year":"2001","journal-title":"Journal of computational chemistry"},{"issue":"7","key":"pone.0283743.ref052","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data","volume":"9","author":"DR Roe","year":"2013","journal-title":"Journal of chemical theory and computation"},{"issue":"6","key":"pone.0283743.ref053","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1073\/pnas.40.6.377","article-title":"Radial distribution functions of some structures of the polypeptide chain","volume":"40","author":"J. Donohue","year":"1954","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"pone.0283743.ref054","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0924-2031(99)00014-4","article-title":"Deriving the 3D structure of organic molecules from their infrared spectra","volume":"19","author":"MC Hemmer","year":"1999","journal-title":"Vibrational spectroscopy"},{"issue":"9","key":"pone.0283743.ref055","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA. py: an efficient program for end-state free energy calculations","volume":"8","author":"BR Miller","year":"2012","journal-title":"Journal of chemical theory and computation"},{"issue":"2","key":"pone.0283743.ref056","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/minf.201100135","article-title":"Free energy calculations by the molecular mechanics Poisson\u2212 Boltzmann surface area method","volume":"31","author":"N Homeyer","year":"2012","journal-title":"Molecular informatics"},{"issue":"12","key":"pone.0283743.ref057","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":"PA Kollman","year":"2000","journal-title":"Accounts of chemical research"},{"issue":"11","key":"pone.0283743.ref058","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/14786440109462720","article-title":"LIII. On lines and planes of closest fit to systems of points in space","volume":"2","author":"K. Pearson","year":"1901","journal-title":"The London, Edinburgh, and Dublin philosophical magazine and journal of science"},{"issue":"1\u20133","key":"pone.0283743.ref059","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0169-7439(87)80084-9","article-title":"Principal component analysis","volume":"2","author":"S Wold","year":"1987","journal-title":"Chemometrics and intelligent laboratory systems"},{"issue":"7","key":"pone.0283743.ref060","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1021\/jp9536920","article-title":"Principal component analysis and long time protein dynamics","volume":"100","author":"MA Balsera","year":"1996","journal-title":"The Journal of Physical Chemistry"},{"issue":"24","key":"pone.0283743.ref061","doi-asserted-by":"crossref","first-page":"12B640_1","DOI":"10.1063\/1.4938249","article-title":"Contact-and distance-based principal component analysis of protein dynamics","volume":"143","author":"M Ernst","year":"2015","journal-title":"The Journal of chemical physics"},{"issue":"20","key":"pone.0283743.ref062","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1093\/bioinformatics\/btab187","article-title":"ProDy 2.0: increased scale and scope after 10 years of protein dynamics modelling with Python","volume":"37","author":"S Zhang","year":"2021","journal-title":"Bioinformatics"},{"issue":"03","key":"pone.0283743.ref063","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","author":"JD Hunter","year":"2007","journal-title":"Computing in science & engineering"},{"issue":"2","key":"pone.0283743.ref064","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1021\/jm2014293","article-title":"Peroxisome proliferator-activated receptors (PPARs) have multiple binding points that accommodate ligands in various conformations: phenylpropanoic acid-type PPAR ligands bind to PPAR in different conformations, depending on the subtype","volume":"55","author":"N Kuwabara","year":"2012","journal-title":"Journal of medicinal chemistry"},{"key":"pone.0283743.ref065","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.3389\/fphar.2018.01275","article-title":"QSAR-based virtual screening: advances and applications in drug discovery","volume":"9","author":"BJ Neves","year":"2018","journal-title":"Frontiers in pharmacology"},{"issue":"5","key":"pone.0283743.ref066","doi-asserted-by":"crossref","first-page":"e33643","DOI":"10.1371\/journal.pone.0033643","article-title":"Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding","volume":"7","author":"FA Batista","year":"2012","journal-title":"PloS one"},{"key":"pone.0283743.ref067","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1097\/00005344-199310000-00016","article-title":"Pharmacology of SC-52458, an Orally Active, Nonpeptide Angiotensin AT~ 1 Receptor Antagonist","volume":"22","author":"GM Olins","year":"1993","journal-title":"Journal of cardiovascular pharmacology"},{"issue":"2","key":"pone.0283743.ref068","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2165\/00003088-200241020-00005","article-title":"Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers","volume":"41","author":"C Csajka","year":"2002","journal-title":"Clinical pharmacokinetics"},{"key":"pone.0283743.ref069","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1016\/0959-8049(96)88251-7","article-title":"\u2018Tomudex\u2019(ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia","volume":"32","author":"D Cunningham","year":"1996","journal-title":"European Journal of 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Keating","year":"2017","journal-title":"Drugs"},{"issue":"6","key":"pone.0283743.ref073","doi-asserted-by":"crossref","first-page":"3174","DOI":"10.1167\/iovs.09-5078","article-title":"The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs","volume":"52","author":"CJ Murphy","year":"2011","journal-title":"Investigative ophthalmology & visual science"},{"issue":"4","key":"pone.0283743.ref074","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1089\/jop.2012.0102","article-title":"Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118)","volume":"29","author":"Y Sun","year":"2013","journal-title":"Journal of ocular pharmacology and therapeutics"},{"issue":"4","key":"pone.0283743.ref075","doi-asserted-by":"crossref","first-page":"194","DOI":"10.4103\/0976-500X.195920","article-title":"Lifitegrast: a novel drug for treatment of dry eye disease","volume":"7","author":"A Abidi","year":"2016","journal-title":"Journal of Pharmacology and Pharmacotherapeutics"},{"issue":"25","key":"pone.0283743.ref076","doi-asserted-by":"crossref","first-page":"18625","DOI":"10.1074\/jbc.M702538200","article-title":"Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor \u03b3","volume":"282","author":"AL Ambrosio","year":"2007","journal-title":"Journal of Biological Chemistry"},{"issue":"10","key":"pone.0283743.ref077","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.str.2007.07.014","article-title":"Partial agonists activate PPAR\u03b3 using a helix 12 independent mechanism","volume":"15","author":"JB Bruning","year":"2007","journal-title":"Structure"},{"issue":"2","key":"pone.0283743.ref078","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1006\/jmbi.2000.3636","article-title":"Ligand-induced stabilization of PPAR\u03b3 monitored by NMR spectroscopy: implications for nuclear receptor activation","volume":"298","author":"BA Johnson","year":"2000","journal-title":"Journal of molecular biology"},{"issue":"13","key":"pone.0283743.ref079","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1016\/j.bmc.2019.05.028","article-title":"2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator pharmacophore","volume":"27","author":"S Ahn","year":"2019","journal-title":"Bioorganic & Medicinal Chemistry"},{"issue":"8","key":"pone.0283743.ref080","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S0969-2126(01)00634-7","article-title":"Structure of the PPAR\u03b1 and-\u03b3 ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family","volume":"9","author":"P Cronet","year":"2001","journal-title":"Structure"},{"issue":"13","key":"pone.0283743.ref081","first-page":"E2563","article-title":"Structural basis for specific 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