{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:38:08Z","timestamp":1792607888941,"version":"4.5.0"},"reference-count":83,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia","doi-asserted-by":"publisher","award":["RU029-2014\/5526306"],"award-info":[{"award-number":["RU029-2014\/5526306"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004386","name":"Universiti Malaya","doi-asserted-by":"publisher","award":["RU029-2014\/5526306"],"award-info":[{"award-number":["RU029-2014\/5526306"]}],"id":[{"id":"10.13039\/501100004386","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Folate receptor alpha (FR\u03b1) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FR\u03b1 active site provides a basis for designing more specific targets for FR\u03b1. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FR\u03b1. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FR\u03b1 pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FR\u03b1 pocket were smaller than the FA\u2013FR\u03b1 system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.<\/jats:p>","DOI":"10.3390\/molecules26041079","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T20:56:21Z","timestamp":1613681781000},"page":"1079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FR\u03b1. an In Silico Insight"],"prefix":"10.3390","volume":"26","author":[{"given":"Mohammad G.","family":"Al-Thiabat","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"},{"name":"Pharmaceutical Design and Simulation (PhDS) Laboratory, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9120-6631","authenticated-orcid":false,"given":"Fadi G.","family":"Saqallah","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"},{"name":"Pharmaceutical Design and Simulation (PhDS) Laboratory, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4469-1969","authenticated-orcid":false,"given":"Amirah Mohd","family":"Gazzali","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noratiqah","family":"Mohtar","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2156-7682","authenticated-orcid":false,"given":"Beow Keat","family":"Yap","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-2073","authenticated-orcid":false,"given":"Yee Siew","family":"Choong","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8353-8679","authenticated-orcid":false,"given":"Habibah A","family":"Wahab","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"},{"name":"Pharmaceutical Design and Simulation (PhDS) Laboratory, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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