{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:27:12Z","timestamp":1791354432727,"version":"4.3.1"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T00:00:00Z","timestamp":1549843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This research was supported by the Bio &amp; Medical Technology Development Program of the National Research Foundation (NRF) &amp; funded by the Korean government (MSIT) and also supported by Basic Science Research Program (2017R1D1A3B03035738) through the Natio","award":["No. NRF-2018M3A9A7057263"],"award-info":[{"award-number":["No. NRF-2018M3A9A7057263"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of human DHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cell proliferation. In the current study, ligand-based pharmacophore modeling identified and evaluated the critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generated from known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS) deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features, including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and one hydrophobic (HYP). Hypo1 was validated using Fischer\u2019s randomization, test set, and decoy set validations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex, National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test and Lipinski\u2019s rule of five, where the drug-like hit compounds were identified. The hit compounds were docked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67 (docking score for the reference compound), clustering analysis, and hydrogen bond interactions were identified. Furthermore, molecular dynamics (MD) simulation identified three compounds as the best inhibitors of hDHFR with the lowest root mean square deviation (1.2 \u00c5 to 1.8 \u00c5), hydrogen bond interactions with hDHFR, and low binding free energy (\u2212127 kJ\/mol to \u2212178 kJ\/mol). Finally, the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFR in human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoid arthritis chemotherapeutics.<\/jats:p>","DOI":"10.3390\/jcm8020233","type":"journal-article","created":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T03:18:20Z","timestamp":1549941500000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["In Silico Study Probes Potential Inhibitors of Human Dihydrofolate Reductase for Cancer Therapeutics"],"prefix":"10.3390","volume":"8","author":[{"given":"Rabia","family":"Rana","sequence":"first","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailima","family":"Rampogu","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Zeb","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minky","family":"Son","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanin","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gihwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghwa","family":"Yoon","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayoung","family":"Baek","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9279-2620","authenticated-orcid":false,"given":"Sarvanan","family":"Parameswaran","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Busan Paik Hospital, Inje University, Busan 47392, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keun","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tobias, A.M., Toska, D., Lange, K., Eck, T., Bhat, R., Janson, C.A., Rotella, D.P., Gubler, U., and Goodey, N.M. 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