{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:02:01Z","timestamp":1792015321155,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"A*STAR BMRC Strategic Positioning Fund (SPF)-A*STAR-P&amp;G Collaboration Grant","award":["H23HW10006"],"award-info":[{"award-number":["H23HW10006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niacinamide, a derivative of vitamin B3, has been shown to reduce skin pigmentation (i.e., acting as a brightening agent) and inflammatory responses such as dermatitis and acne vulgaris. However, niacinamide is a hydrophilic compound and poor partitioning to the lipid matrix in the uppermost layer of the skin (the stratum corneum or SC) limits its delivery to the skin. This necessitates the use of penetration enhancers to increase its bio-availability. In this study, we used computer simulations to investigate the skin penetration of niacinamide alone and in combination with other brightening agents that are also shown to be skin penetration enhancers, namely undecylenoyl phenylalanine (Sepiwhite\u00ae), bisabolol, or sucrose dilaurate. Molecular dynamics simulations were performed to reveal molecular interactions of these brightening agents with a lipid bilayer model that mimics the SC lipid matrix. We observed minimal penetration of niacinamide into the SC lipid bilayer when applied alone or in combination with any one of the three compounds. However, when all three compounds were combined, a notable increase in penetration was observed. We showed a 32% increase in the niacinamide diffusivity in the presence of three other brightening agents, which also work as penetration enhancers for niacinamide. These findings suggest that formulations containing multiple brightening agents, which work as penetration enhancers, may improve skin penetration of niacinamide and enhance the effectiveness of the treatment.<\/jats:p>","DOI":"10.3390\/ijms26041555","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:25:57Z","timestamp":1739355957000},"page":"1555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhancing Niacinamide Skin Penetration via Other Skin Brightening Agents: A Molecular Dynamics Simulation Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Kamolrat","family":"Somboon","sequence":"first","affiliation":[{"name":"Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3707-8747","authenticated-orcid":false,"given":"Choon-Peng","family":"Chng","sequence":"additional","affiliation":[{"name":"School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1941-1200","authenticated-orcid":false,"given":"Changjin","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0500-1080","authenticated-orcid":false,"given":"Shikhar","family":"Gupta","sequence":"additional","affiliation":[{"name":"P&G Singapore Innovation Center (SgIC), 70 Biopolis Street, Singapore 138547, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"ref_1","first-page":"285","article-title":"A Review of the Range of Effects of Niacinamide in Human Skin","volume":"5","author":"Matts","year":"2002","journal-title":"Int. Fed. Soc. Cosmet. Chem. Mag."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Boo, Y.C. (2021). Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation. Antioxidants, 10.","DOI":"10.3390\/antiox10081315"},{"key":"ref_3","first-page":"29","article-title":"Topical Niacinamide 4% and Desonide 0.05% for Treatment of Axillary Hyperpigmentation: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"6","author":"Smoller","year":"2013","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/sj.bjp.0702009","article-title":"Inhibitors of the Activity of Poly (ADP-Ribose) Synthetase Reduce the Cell Death Caused by Hydrogen Peroxide in Human Cardiac Myoblasts","volume":"124","author":"Bowes","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/j.1365-2133.2000.03705.x","article-title":"Nicotinamide Increases Biosynthesis of Ceramides as Well as Other Stratum Corneum Lipids to Improve the Epidermal Permeability Barrier","volume":"143","author":"Tanno","year":"2000","journal-title":"Br. J. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1111\/ijd.12002","article-title":"Topical 4% Nicotinamide vs. 1% Clindamycin in Moderate Inflammatory Acne Vulgaris","volume":"52","author":"Khodaeiani","year":"2013","journal-title":"Int. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e13475","DOI":"10.1111\/srt.13475","article-title":"A Single-Center, Randomized, Controlled Study on the Efficacy of Niacinamide-Containing Body Emollients Combined with Cleansing Gel in the Treatment of Mild Atopic Dermatitis","volume":"29","author":"Zhu","year":"2023","journal-title":"Skin Res. Technol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1046\/j.1365-2133.2002.04834.x","article-title":"The Effect of Niacinamide on Reducing Cutaneous Pigmentation and Suppression of Melanosome Transfer","volume":"147","author":"Hakozaki","year":"2002","journal-title":"Br. J. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/j.0906-6705.2005.00309.x","article-title":"Effective Inhibition of Melanosome Transfer to Keratinocytes by Lectins and Niacinamide Is Reversible","volume":"14","author":"Greatens","year":"2005","journal-title":"Exp. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3109\/09546634.2013.814754","article-title":"Topical Nicotinamide for Seborrheic Dermatitis: An Open Randomized Study","volume":"25","author":"Fabbrocini","year":"2014","journal-title":"J. Dermatol. Treat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1046\/j.1365-2249.2003.02031.x","article-title":"Nicotinamide is a Potent Inhibitor of Proinflammatory Cytokines","volume":"131","author":"Ungerstedt","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1038\/jid.1983.12","article-title":"Epidermal Lipids, Barrier Function, and Desquamation","volume":"80","author":"Elias","year":"1983","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/1523-1747.ep12687968","article-title":"Mammalian Epidermal Barrier Layer Lipids: Composition and Influence on Structure","volume":"69","author":"Elias","year":"1977","journal-title":"J. Investig. Dermatol."},{"key":"ref_14","first-page":"175","article-title":"Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects","volume":"13","author":"Brown","year":"2006","journal-title":"Drug Deliv. J. Deliv. Target. Ther. Agents"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s11095-013-1169-2","article-title":"In Vitro-in Vivo Correlation in Skin Permeation","volume":"31","author":"Mohammed","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Kung, C.P., Sil, B.C., Lane, M.E., Hadgraft, J., Heinrich, M., and Sinko, B. (2019). Topical Delivery of Niacinamide: Influence of Binary and Ternary Solvent Systems. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11120668"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dragicevic, N., and Maibach, H.I. (2015). Surfactants as Penetration Enhancers for Dermal and Transdermal Drug Delivery. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum, Springer.","DOI":"10.1007\/978-3-662-47039-8"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.jsps.2023.05.018","article-title":"Development and Evaluation of Niacinamide Transdermal Formulation by Artificial Membrane Permeability","volume":"31","author":"Sohn","year":"2023","journal-title":"Saudi Pharm. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8987","DOI":"10.1021\/acs.jpcb.6b05451","article-title":"Molecular Dynamics Simulation Study of Permeation of Molecules through Skin Lipid Bilayer","volume":"120","author":"Gupta","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jconrel.2018.05.026","article-title":"Predicting Drug Permeability through Skin Using Molecular Dynamics Simulation","volume":"283","author":"Lundborg","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4900","DOI":"10.1021\/acs.jcim.3c00625","article-title":"Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations","volume":"63","author":"Wennberg","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1021\/acs.jpcb.3c06784","article-title":"Mechanisms of the Drug Penetration Enhancer Propylene Glycol Interacting with Skin Lipid Membranes","volume":"128","author":"Mistry","year":"2024","journal-title":"J. Phys. Chem. B"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fang, B., Card, P.D., Chen, J., Li, L., Laughlin, T., Jarrold, B., Zhao, W., Benham, A.M., M\u00e4\u00e4tt\u00e4, A.T., and Hawkins, T.J. (2022). A Potential Role of Keratinocyte-Derived Bilirubin in Human Skin Yellowness and Its Amelioration by Sucrose Laurate\/Dilaurate. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23115884"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1773-2247(11)50066-8","article-title":"Penetration Enhancer Effect of Sucrose Laurate and Transcutol on Ibuprofen","volume":"21","author":"Csizmazia","year":"2011","journal-title":"J. Drug Del. Sci. Tech."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0378-5173(98)00292-0","article-title":"Bicontinuous Sucrose Ester Microemulsion: A New Vehicle for Topical Delivery of Niflumic Acid","volume":"176","author":"Bolzinger","year":"1998","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/0021-9797(82)90214-4","article-title":"Interaction of Polyoxyethylene Alkyl Ethers with Cholesterol Monolayers 1","volume":"89","author":"Walters","year":"1982","journal-title":"J. Colloid Interface Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6061","DOI":"10.1111\/jocd.15102","article-title":"Preparation, Characterization, and Evaluation of Anti-Tyrosinase Activity of Solid Lipid Nanoparticles Containing Undecylenoyl Phenylalanine (Sepiwhite\u00ae)","volume":"21","author":"Kabiri","year":"2022","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/jocd.12089","article-title":"A Double-Blind Vehicle-Controlled Study of a Preparation Containing Undecylenoyl Phenylalanine 2% in the Treatment of Melasma in Females","volume":"13","author":"Katoulis","year":"2014","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1473-2165.2009.00470.x","article-title":"Reduction in the Appearance of Facial Hyperpigmentation by Topical N-Undecyl-10-Enoyl-L-Phenylalanine and Its Combination with Niacinamide","volume":"8","author":"Bissett","year":"2009","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.archoralbio.2012.08.001","article-title":"The Antimicrobial Activity of Alpha-Bisabolol and Tea Tree Oil against Solobacterium Moorei, a Gram-Positive Bacterium Associated with Halitosis","volume":"58","author":"Forrer","year":"2013","journal-title":"Arch. Oral. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.fitote.2010.09.012","article-title":"(-)-\u03b1-Bisabolol Attenuates Visceral Nociception and Inflammation in Mice","volume":"82","author":"De","year":"2011","journal-title":"Fitoterapia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"173","DOI":"10.2174\/1389201015666140528152946","article-title":"\u03b1-(-)-Bisabolol Reduces Pro-Inflammatory Cytokine Production and Ameliorates Skin Inflammation","volume":"15","author":"Maurya","year":"2014","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1468-2494.2010.00560.x","article-title":"Whitening Effect of \u03b1-Bisabolol in Asian Women Subjects","volume":"32","author":"Lee","year":"2010","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0378-5173(91)90167-M","article-title":"Alpha-Bisabolol, a Possible Safe Penetration Enhancer for Dermal and Transdermal Therapeutics","volume":"70","author":"Kadir","year":"1991","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102213","DOI":"10.1016\/j.eml.2024.102213","article-title":"Palmitoylation Enhances Short Polar Peptide Permeation across Stratum Corneum Lipid Bilayer: A Molecular Dynamics Study","volume":"71","author":"Chng","year":"2024","journal-title":"Extreme Mech. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1002\/jcc.21224","article-title":"Packmol: A Package for Building Initial Configurations for Molecular Dynamics Simulations","volume":"30","author":"Martinez","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM Simulations Using the CHARMM36 Additive Force Field","volume":"12","author":"Lee","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_40","unstructured":"Markidis, S., and Laure, E. Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS. Proceedings of the Solving Software Challenges for Exascale."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/bioinformatics\/btt055","article-title":"GROMACS 4.5: A High-Throughput and Highly Parallel Open Source Molecular Simulation Toolkit","volume":"29","author":"Pronk","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/bioinformatics\/btw563","article-title":"FATSLiM: A Fast and Robust Software to Analyze MD Simulations of Membranes","volume":"33","author":"Buchoux","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1002\/jcc.24829","article-title":"CHARMM-GUI Ligand Reader and Modeler for CHARMM Force Field Generation of Small Molecules","volume":"38","author":"Kim","year":"2017","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:32:20Z","timestamp":1760027540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26041555"],"URL":"https:\/\/doi.org\/10.3390\/ijms26041555","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,12]]}}}