{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:34:32Z","timestamp":1789104872550,"version":"build-2803163510"},"reference-count":63,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Neutrophil cells\u2019 lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies. Methods: We utilized Maestro Schr\u00f6dinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199\u2014an investigational compound\u2014as a positive control for the docked molecules. Preparation of the protein was performed by Schr\u00f6dinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schr\u00f6dinger Release 2021\u20133:Schr\u00f6dinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed. Results\/Conclusions: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values \u221211.617, \u221210.599, \u221210.521, \u22129.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors.<\/jats:p>","DOI":"10.3390\/metabo15030156","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T12:01:17Z","timestamp":1740484877000},"page":"156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Multifaceted Computational Approach to Identify PAD4 Inhibitors for the Treatment of Rheumatoid Arthritis (RA)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7702-9379","authenticated-orcid":false,"given":"Mansour S.","family":"Alturki","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2112-9092","authenticated-orcid":false,"given":"Mohamed S.","family":"Gomaa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9178-9021","authenticated-orcid":false,"given":"Nada","family":"Tawfeeq","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0079-8646","authenticated-orcid":false,"given":"Abdulaziz H.","family":"Al Khzem","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsina B.","family":"Shaik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murtadha","family":"Alshaikh Jafar","sequence":"additional","affiliation":[{"name":"College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alsamen","sequence":"additional","affiliation":[{"name":"College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Al Nahab","sequence":"additional","affiliation":[{"name":"College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Al-Eid","sequence":"additional","affiliation":[{"name":"College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4144-6388","authenticated-orcid":false,"given":"Alhassan","family":"Almutawah","sequence":"additional","affiliation":[{"name":"College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8585-0888","authenticated-orcid":false,"given":"Thankhoe A.","family":"Rants\u2019o","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled A. G.","family":"Ayil","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Chemistry, Faculty of Science, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4929-7071","authenticated-orcid":false,"given":"Mohammed","family":"Almaghrabi","sequence":"additional","affiliation":[{"name":"Pharmacognosy and Pharmaceutical Chemistry Department, Faculty of Pharmacy, Taibah University, Al Madinah Al Munawarah 30001, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1002\/bies.10357","article-title":"PAD, a Growing Family of Citrullinating Enzymes: Genes, Features and Involvement in Disease","volume":"25","author":"Vossenaar","year":"2003","journal-title":"BioEssays"},{"key":"ref_2","first-page":"616","article-title":"Protein Arginine Deiminase 4 (PAD4): Current Understanding and Future Therapeutic Potential","volume":"12","author":"Jones","year":"2009","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"700","DOI":"10.2174\/1389450116666150202160954","article-title":"Protein arginine deiminases and associated citrullination: Physiological functions and diseases associated with dysregulation","volume":"16","author":"Witalison","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1006\/bbrc.1998.8148","article-title":"Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages","volume":"243","author":"Asaga","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/14728222.2017.1294160","article-title":"PAD4: Pathophysiology, current therapeutics and future perspective in rheumatoid arthritis","volume":"21","author":"Koushik","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1021\/acsmedchemlett.2c00387","article-title":"Novel Peptidylarginine Deiminase Type 4 (PAD4) Inhibitors","volume":"13","author":"Sabnis","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/47412","article-title":"The language of covalent histone modifications","volume":"403","author":"Strahl","year":"2000","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1756-8935-3-22","article-title":"Global turnover of histone post-translational modifications and variants in human cells","volume":"3","author":"Zee","year":"2010","journal-title":"Epigenetics Chromatin"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/bip.22127","article-title":"The protein arginine deiminases: Structure, function, inhibition, and disease","volume":"99","author":"Bicker","year":"2013","journal-title":"Biopolymers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nsmb799","article-title":"Structural basis for Ca2+-induced activation of human PAD4","volume":"11","author":"Arita","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cherrington, B.D., Morency, E., Struble, A.M., Coonrod, S.A., and Wakshlag, J.J. (2010). Potential role for peptidylarginine deiminase 2 (PAD2) in citrullination of canine mammary epithelial cell histones. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011768"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/NEN.0b013e318207559e","article-title":"Subcellular localization of peptidylarginine deiminase 2 and citrullinated proteins in brains of scrapie-infected mice: Nuclear localization of PAD2 and membrane fraction-enriched citrullinated proteins","volume":"70","author":"Jang","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1136\/ard.2011.151712","article-title":"Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis","volume":"71","author":"Darrah","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.4049\/jimmunol.166.6.4177","article-title":"The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the \u03b1-and \u03b2-chains of fibrin","volume":"166","author":"Sebbag","year":"2001","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.tcb.2022.01.014","article-title":"Insights into peptidylarginine deiminase expression and citrullination pathways","volume":"32","author":"Yu","year":"2022","journal-title":"Trends Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s41584-020-0409-1","article-title":"PAD enzymes in rheumatoid arthritis: Pathogenic effectors and autoimmune targets","volume":"16","author":"Curran","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113840","DOI":"10.1016\/j.ejmech.2021.113840","article-title":"Peptidylarginine deiminases 4 as a promising target in drug discovery","volume":"226","author":"Yang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1080\/1744666X.2020.1668778","article-title":"Autoantibodies to protein-arginine deiminase (PAD) 4 in rheumatoid arthritis: Immunological and clinical significance, and potential for precision medicine: Anti-PAD4 antibodies in RA","volume":"15","author":"Palterer","year":"2019","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Damgaard, D., Bawadekar, M., Senolt, L., Stensballe, A., Shelef, M.A., and Nielsen, C.H. (2018). Relative efficiencies of peptidylarginine deiminase 2 and 4 in generating target sites for anti-citrullinated protein antibodies in fibrinogen, alpha-enolase and histone H3. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203214"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mart\u00edn Monreal, M.T., Rebak, A.S., Massarenti, L., Mondal, S., \u0160enolt, L., \u00d8dum, N., Nielsen, M.L., Thompson, P.R., Nielsen, C.H., and Damgaard, D. (2021). Applicability of small-molecule inhibitors in the study of peptidyl arginine deiminase 2 (PAD2) and PAD4. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.716250"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jmgm.2014.10.014","article-title":"Theoretical study of the mechanism of protein arginine deiminase 4 (PAD4) inhibition by F-amidine","volume":"55","author":"Li","year":"2015","journal-title":"J. Mol. Graph. Model."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1021\/bi061180d","article-title":"Inhibitors and inactivators of protein arginine deiminase 4: Functional and structural characterization","volume":"45","author":"Luo","year":"2006","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1021\/ja0576233","article-title":"A fluoroacetamidine-based inactivator of protein arginine deiminase 4: Design, synthesis, and in vitro and in vivo evaluation","volume":"128","author":"Luo","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/nchembio.1735","article-title":"Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation","volume":"11","author":"Lewis","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1021\/cb200258q","article-title":"Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors","volume":"7","author":"Jones","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6919","DOI":"10.1021\/jm2008985","article-title":"The development of N-\u03b1-(2-carboxyl) benzoyl-N 5-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-\u03b1-(2-carboxyl) benzoyl-N 5-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine). As second-generation protein arginine deiminase (PAD) inhibitors","volume":"54","author":"Causey","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.bmc.2007.10.021","article-title":"Profiling Protein Arginine Deiminase 4 (PAD4): A novel screen to identify PAD4 inhibitors","volume":"16","author":"Knuckley","year":"2008","journal-title":"Bioorganic Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/cei.13556","article-title":"Citrullinated inter-alpha-trypsin inhibitor heavy chain 4 in arthritic joints and its potential effect in the neutrophil migration","volume":"203","author":"Osada","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_29","first-page":"184","article-title":"Understanding the role of peptidylarginine deiminases (PADs) in diseases and their inhibitors as potential therapeutic agents","volume":"4","author":"Ali","year":"2017","journal-title":"Eur. J. Pharm. Med. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ahmad, F., Albutti, A., Tariq, M.H., Din, G., Tahir ul Qamar, M., and Ahmad, S. (2022). Discovery of potential antiviral compounds against hendra virus by targeting its receptor-binding protein (G) using computational approaches. Molecules, 27.","DOI":"10.3390\/molecules27020554"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2013ligand discovery for everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: A software program for pK a prediction and protonation state generation for drug-like molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jaundoo, R., Bohmann, J., Gutierrez, G.E., Klimas, N., Broderick, G., and Craddock, T.J. (2018). Using a consensus docking approach to predict adverse drug reactions in combination drug therapies for gulf war illness. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113355"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Aldholmi, M., Ahmad, R., Shaikh, M.H., Salem, A.M., Alqurashi, M., and Alturki, M. (2024). Anti-Infective Activity of Momordica charantia Extract with Molecular Docking of Its Triterpenoid Glycosides. Antibiotics, 13.","DOI":"10.3390\/antibiotics13060544"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alturki, M.S. (2024). Exploring marine-derived compounds: In silico discovery of selective ketohexokinase (KHK) inhibitors for metabolic disease therapy. Mar. Drugs, 22.","DOI":"10.3390\/md22100455"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"108054","DOI":"10.1016\/j.jmgm.2021.108054","article-title":"Optimization of covalent docking for organophosphates interaction with Anopheles acetylcholinesterase","volume":"110","year":"2022","journal-title":"J. Mol. Graph. Model."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1111\/jcpt.13787","article-title":"Acinetobacter baumannii: Pathogenesis, virulence factors, novel therapeutic options and mechanisms of resistance to antimicrobial agents with emphasis on tigecycline","volume":"47","author":"Dehbanipour","year":"2022","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1023\/A:1008763014207","article-title":"Combined molecular mechanical and continuum solvent approach (MM-PBSA\/GBSA) to predict ligand binding","volume":"18","author":"Massova","year":"2000","journal-title":"Perspect. Drug Discov. Des."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1517\/14656566.2012.729820","article-title":"Therapeutic options for Acinetobacter baumannii infections: An update","volume":"13","author":"Vila","year":"2012","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.ijantimicag.2015.03.001","article-title":"Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology","volume":"45","author":"Potron","year":"2015","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kumar, A., and Zhang, K.Y.J. (2018). Advances in the development of shape similarity methods and their application in drug discovery. Front. Chem., 6.","DOI":"10.3389\/fchem.2018.00315"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11623","DOI":"10.1021\/j100096a001","article-title":"Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields","volume":"98","author":"Stephens","year":"1994","journal-title":"J. Phys. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1063\/1.448975","article-title":"Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals","volume":"82","author":"Hay","year":"1985","journal-title":"J. Chem. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Domingo, L., R\u00edos-Guti\u00e9rrez, M., and P\u00e9rez, P. (2016). Applications of the Conceptual Density Functional Theory Indices to Organic Chemistry Reactivity. Molecules, 21.","DOI":"10.3390\/molecules21060748"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"PR46","DOI":"10.1021\/cr078014b","article-title":"Update 1 of: Electrophilicity index","volume":"107","author":"Chattaraj","year":"2007","journal-title":"Chem. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1021\/cr990029p","article-title":"Conceptual density functional theory","volume":"103","author":"Geerlings","year":"2003","journal-title":"Chem. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1021\/ja0276063","article-title":"HSAB principle applied to the time evolution of chemical reactions","volume":"125","author":"Chattaraj","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8440","DOI":"10.1073\/pnas.83.22.8440","article-title":"Absolute electronegativity and hardness correlated with molecular orbital theory","volume":"83","author":"Pearson","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1021\/jo00267a034","article-title":"Absolute electronegativity and hardness: Applications to organic chemistry","volume":"54","author":"Pearson","year":"1989","journal-title":"J. Org. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1063\/1.1740412","article-title":"Molecular orbital theory of orientation in aromatic, heteroaromatic, and other conjugated molecules","volume":"22","author":"Fukui","year":"1954","journal-title":"J. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11283","DOI":"10.1021\/jp021152e","article-title":"HOMO\u2212LUMO gap as an index of molecular size and structure for polycyclic aromatic hydrocarbons (PAHs) and asphaltenes: A theoretical study. I","volume":"106","year":"2002","journal-title":"J. Phys. Chem. A"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0166-1280(97)00162-0","article-title":"Statistical analysis of the molecular surface electrostatic potential: An approach to describing noncovalent interactions in condensed phases","volume":"425","author":"Murray","year":"1998","journal-title":"J. Mol. Struct. THEOCHEM"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1063\/1.1740588","article-title":"Electronic population analysis on LCAO\u2013MO molecular wave functions. I","volume":"23","author":"Mulliken","year":"1955","journal-title":"J. Chem. Phys."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1021\/ci2002704","article-title":"Rapid shape-based ligand alignment and virtual screening method based on atom\/feature-pair similarities and volume overlap scoring","volume":"51","author":"Sastry","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Rosales-L\u00f3pez, A., L\u00f3pez-Castillo, G.N., Sandoval-Ram\u00edrez, J., Ter\u00e1n, J.L., and Carrasco-Carballo, A. (2024). Correlation between Molecular Docking and the Stabilizing Interaction of HOMO-LUMO: Spirostans in CHK1 and CHK2, an In Silico Cancer Approach. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168588"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gheidari, D., Morteza, M., and Foroozan, H. (2024). Virtual screening, molecular docking, MD simulation studies, DFT calculations, ADMET, and drug likeness of Diaza-adamantane as potential MAPKERK inhibitors. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1360226"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"27089","DOI":"10.1021\/acsomega.1c03668","article-title":"1, 2, 3-Triazoles of 8-hydroxyquinoline and HBT: Synthesis and studies (DNA binding, antimicrobial, molecular docking, ADME, and DFT)","volume":"6","author":"Nehra","year":"2021","journal-title":"ACS Omega"},{"key":"ref_62","first-page":"301","article-title":"Design, synthesis, molecular modeling, anticancer studies, and density functional theory calculations of 4-(1, 2, 4-triazol-3-ylsulfanylmethyl)-1, 2, 3-triazole derivatives","volume":"6","author":"Khan","year":"2020","journal-title":"ACS Omega"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1021\/jp052111w","article-title":"Koopmans-like approximation in the Kohn\u2212 Sham method and the impact of the frozen core approximation on the computation of the reactivity parameters of the density functional theory","volume":"109","author":"Vargas","year":"2005","journal-title":"J. Phys. Chem. A"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/3\/156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:42:26Z","timestamp":1760028146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/3\/156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,25]]},"references-count":63,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["metabo15030156"],"URL":"https:\/\/doi.org\/10.3390\/metabo15030156","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,25]]}}}