Abstract
In the present investigation, computations based on density functional theory (DFT) were employed to scrutinize the molecular configurations of clascosterone. Optimization was achieved using the DFT/B3LYP method with the 6-31G (d,p) basis set to thoroughly explore its structural and spectroscopic features. Additionally, molecular electrostatic potential (MEP) and Mulliken population analyses were conducted to comprehend the bonding characteristics and reactive sites. The Hirshfeld surface highlighted predominant H•••H interactions (71.5%), followed by O•••H interactions (25.5%). The stability of the compound was confirmed through the determination of hyperconjugative interactions using Natural Bond Orbital (NBO) analysis. Furthermore, molecular docking assessed the potential biological significance of clascosterone as an antitumor agent, targeting SMAD proteins like SMAD3 and SMAD4, resulting in binding energies of -8.22 and -8.57 kcal/mol, respectively.
Keywords
Clascosterone, DFT, NBO, MEP, Antitumor agent,Downloads
References
- S.M. Tuchayi, E. Makrantonaki, R. Ganceviciene, C. Dessinioti, S.R. Feldman, C.C Zouboulis, Acne vulgaris. Nature Reviews Disease primers, 1(1), (2015) 1-20. https://doi.org/10.1038/nrdp.2015.29
- D.D Lynn, T. Umari, C.A. Dunnick, R.P. Dellavalle, The epidemiology of acne vulgaris in late adolescence. Adolescent health, medicine and therapeutics, 7, (2016) 13-25. https://doi.org/10.2147/AHMT.S55832
- J.K. Tan, K. Bhate, A global perspective on the epidemiology of acne. British Journal of Dermatology, 172(S1), (2015) 3-12. https://doi.org/10.1111/bjd.13462
- J.Q. Del Rosso, L.H. Kircik, D. Thiboutot, Androgens, Androgen Receptors, and the Skin: From the Laboratory to the Clinic with Emphasis on Clinical and Therapeutic Implications. Journal of drugs in dermatology: JDD, 19(3), (2020) 30-35.
- D. Dart, Androgens have forgotten and emerging roles outside of their reproductive functions, with implications for diseases and disorders. Journal of Endocrine Disorders, 1(1), (2014) 1005.
- M.L. Elsaie, Hormonal treatment of acne vulgaris: an update. Clinical, Cosmetic and Investigational Dermatology, (9), (2016) 241-248. https://doi.org/10.2147/CCID.S114830
- J.J. Lai, P. Chang, K.P. Lai, L. Chen, C. Chang, The role of androgen and androgen receptor in skin-related disorders. Archives of dermatological research, 304, (2012) 499-510. https://doi.org/10.1007/s00403-012-1265-x
- A.M. Layton, E.A. Eady, H. Whitehouse, J.Q. Del Rosso, Z. Fedorowicz, E.J. van Zuuren, Oral spironolactone for acne vulgaris in adult females: a hybrid systematic review. American journal of clinical dermatology, 18 (2017) 169-191. https://doi.org/10.1007/s40257-016-0245-x
- J.Q. Del Rosso, L.H. Kircik, D. Thiboutot, Androgens, Androgen Receptors, and the Skin: From the Laboratory to the Clinic with Emphasis on Clinical and Therapeutic Implications. Journal of drugs in dermatology: JDD, 19(3) (2020) 30-35.
- L.H. Kircik, Androgens and acne: perspectives on clascoterone, the first topical androgen receptor antagonist. Expert Opinion on Pharmacotherapy, 22(13), (2021) 1801-1806. https://doi.org/10.1080/14656566.2021.1918100
- L. Eichenfield, A. Hebert, L.S. Gold, M. Cartwright, E. Fragasso, L. Moro, A. Mazzetti, Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris. Journal of the American Academy of Dermatology, 83(2), (2020) 477-485. https://doi.org/10.1016/j.jaad.2020.04.087
- S.T. Alkhodaidi, K.A. Al Hawsawi, I.T. Alkhudaidi, D. Magzoub, A. Abu‐Zaid, Efficacy and safety of topical clascoterone cream for treatment of acne vulgaris: a systematic review and meta‐analysis of randomized placebo‐controlled trials. Dermatologic Therapy, 34(1) (2021) 14609. https://doi.org/10.1111/dth.14609
- P. Ferraboschi, L. Legnani, G. Celasco, L. Moro, L. Ragonesi, D. Colombo, A full conformational characterization of antiandrogen cortexolone-17α-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy. MedChemComm, 5(7), (2024) 904-914. https://doi.org/10.1039/C4MD00049H
- A. Mazzetti, L. Moro, M. Gerloni, M. Cartwright, Pharmacokinetic profile, safety, and tolerability of clascoterone (cortexolone 17-alpha propionate, CB-03-01) topical cream, 1% in subjects with acne vulgaris: an open-label phase 2a study. Journal of drugs in dermatology: JDD, 18(6), (2019) 563-563.
- A. Hebert, D. Thiboutot, L.S. Gold, M. Cartwright, M. Gerloni, E. Fragasso, A. Mazzetti, Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA dermatology, 156(6), (2020) 621-630. https://doi.org/10.1001/jamadermatol.2020.0465
- C. Rosette, N. Rosette, A. Mazzetti, L. Moro, M. Gerloni, Cortexolone 17α-propionate (clascoterone) is an androgen receptor antagonist in dermal papilla cells in vitro. Journal of drugs in dermatology: JDD, 18(2), (2019) 197-201.
- H.Y. Sun, D.F. Sebaratnam, Clascoterone as a novel treatment for androgenetic alopecia. Clinical and Experimental Dermatology, 45(7), (2020) 913-914. https://doi.org/10.1111/ced.14292
- A. Hargis, M. Yaghi, N.M. Bermudez, H. Lev-Tov, Clascoterone in the treatment of mild hidradenitis suppurativa. Journal of the American Academy of Dermatology, 90(1), (2024) 142-144. https://doi.org/10.1016/j.jaad.2023.08.064
- A. Ram Kumar, C. Senthamil Selvi, S. Selvaraj, G.P. Sheeja Mol, P. Jayaprakash, In silico studies on the molecular geometry, FMO, mulliken charges, MESP, ADME and molecular docking prediction of pyrogallol carboxaldehydes as potential anti-tumour agents, Phys. Chem. Res. 12(2), (2024) 305-320.https://doi.org/10.22036/PCR.2023.402835.2359
- A. Ram Kumar, S. Selvaraj, P. Anthoniammal, R.J. Ramalingam, B. Ranjith, P. Jayaprakash, G.P. Sheeja Mol, Comparison of spectroscopic, structural, and molecular docking studies of 5-nitro-2-fluoroaniline and 2-nitro-5-fluoroaniline: An attempt on fluoroaniline isomers, Journal of Fluorine Chemistry, 270, (2023) 110167. https://doi.org/10.1016/j.jfluchem.2023.110167
- W. Kohn, L.J. Sham, Self-consistent equations including exchange and correlation effects. Physical Review Journals Archive, 140, (1965) A1133–A1138. https://doi.org/10.1103/PhysRev.140.A1133
- A.D. Becke, Density functional thermo chemistry – I: the effect of the exchange only gradient correlation, Journal of Chemical Physics, 98, (1993) 5648–5652. https://doi.org/10.1063/1.462066
- C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density, Physical Review B, 37, (1988) 785–789.
- W.J. Hehre, R. Ditchfield, J.A. Pople, Self—consistent molecular orbital methods. XII. Further extensions of Gaussian—type basis sets for use in molecular orbital studies of organic molecules. The Journal of Chemical Physics, 56(5), (1972) 2257–2261. https://doi.org/10.1103/PhysRevB.37.785
- J.R. Cheeseman, G.W. Trucks, T.A. Keith, M.J. Frisch, A comparison of models for calculating nuclear magnetic resonance shielding tensors. The Journal of Chemical Physics, 104 (1996) 5497–5509, https://doi.org/10.1063/1.471789
- M. Petersilka, U.J. Gossman, E.K.U. Gross, Excitation energies from timedependent density-functional theory. Physical Review Letters, 76, (1996) 1212–1215. https://doi.org/10.1103/PhysRevLett.76.1212
- E. Runge, E.K.U. Gross, Density functional theory for time-dependent systems. Physical Review Letters, 52, (1984) 997. https://doi.org/10.1103/PhysRevLett.52.997
- G.A. Zhurko, D.A. Zhurko, Chemcraft program version 1.6 (Build 315), (2009) http://www.chemcraftprog.com
- S.K. Wolff, D.J. Grimwood, J.J. McKinnon, M.J. Turner, D. Jayatilaka, M.A. Spackman, (2012) Crystal Explorer (Version 3.1), University of Western Australia.
- G.M. Morris, R. Huey, W. Lindstrom, M.F. Sanner, R.K. Belew, D.S. Goodsell, A.J. Olson, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of computational chemistry, 30(16), (2009) 2785-2791. https://doi.org/10.1002/jcc.21256
- W.L. DeLano, Pymol: an open-source molecular graphics tool. CCP4 Newsletter on protein Crystallography, 40(1), (2002) 82–92. http://www.pymol.org
- A.C. Wallace, R.A. Laskowski, J.M. Thornton, LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Engineering, Design and Selection, 8(2), (1995) 127-134. https://doi.org/10.1093/protein/8.2.127
- P. Ferraboschi, M.C. Sala, R. Stradi, L. Ragonesi, C. Gagliardi, P. Lanzarotti, E.M. Ragg, F. Meneghetti, Full spectroscopic characterization of two crystal pseudopolymorphic forms of the antiandrogen cortexolone 17α-propionate for topic application. Steroids, 128, (2017) 95-104.https://dx.doi.org/10.5517/ccdc.csd.cc1l44f9
- A. Ram Kumar, N. Kanagathara, Spectroscopic, structural and molecular docking studies on N, N-dimethyl-2-[6-methyl-2-(4-methylphenyl) imidazo [1, 2-a] pyridin-3-yl] acetamide. Physical Chemistry Research, 12(1), (2024) 95-107. https://doi.org/10.22036/PCR.2023.387911.2306
- A. Ram Kumar, S. Selvaraj, K.S. Jayaprakash, S. Gunasekaran, S. Kumaresan, J. Devanathan, K.A. Selvam, L. Ramadass, M. Mani, P. Rajkumar, Multi-spectroscopic (FT-IR, FT-Raman, 1H NMR and 13C NMR) investigations on syringaldehyde. Journal of Molecular Structure, 1229, (2021) 129490. https://doi.org/10.1016/j.molstruc.2020.129490
- A. Ram Kumar, S. Selvaraj, M. Azam, G.P. Sheeja Mol, N. Kanagathara, M. Alam, P. Jayaprakash, Spectroscopic, biological, and topological insights on lemonol as a potential anticancer agent. ACS Omega, 8(34), (2023) 31548-31566. https://doi.org/10.1021/acsomega.3c04922
- S. Selvaraj, A. Ram Kumar, T. Ahilan, M. Kesavan, G. Serdaroglu, P. Rajkumar, M. Mani, S. Gunasekaran, S. Kumaresan, Experimental and Theoretical Spectroscopic Studies of the Electronic Structure of 2-Ethyl-2-phenylmalonamide. Physical Chemistry Research, 10(3), (2022) 333-344.
- S. Selvaraj, A. Ram Kumar, T. Ahilan, M. Kesavan, S. Gunasekaran, S. Kumaresan, Multi spectroscopic and computational investigations on the electronic structure of oxyclozanide. Journal of the Indian Chemical Society, 99(10), (2022) 100676. https://doi.org/10.1016/j.jics.2022.100676
- A. Ram Kumar, S. Selvaraj, P. Rajkumar, J. Dhanalakshmi, M. Kumar, S.K. Nagarajan, P. Jayaprakash, G.P.S. Mol, S. Awasthi, S.K. Pandey, Insights into structural, vibrational, and chemical shift characteristics, solvents impact (polar and nonpolar) on electronic properties and reactive sites, ADMET predictions, and ligand-protein interactions for antiviral drugs safrole and isosafrole: An in-silico approach. Chemical Physics Impact, 8, (2023) 100443. https://doi.org/10.1016/j.chphi.2023.100443
- K. Thirunavukkarasu, P. Rajkumar, S. Selvaraj, R. Suganya, M. Kesavan, S. Gunasekaran, S. Kumaresan, Vibrational (FT-IR and FT-Raman), electronic (UV-Vis), NMR (1H and 13C) spectra and molecular docking analyses of anticancer molecule 4-hydroxy-3-methoxycinnamaldehyde. Journal of Molecular Structure, 1173, (2018) 307-320. https://doi.org/10.1016/j.molstruc.2018.07.003
- S. Premkumar, A. Jawahar, T. Mathavan, M. Kumara Dhas, V.G. Sathe, A. Milton Franklin Benial, DFT calculation and vibrational spectroscopic studies of 2-(tert-butoxycarbonyl (Boc)-amino)-5-bromopyridin. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 129, (2014) 74-83. https://doi.org/10.1016/j.saa.2014.02.147
- P. Rajkumar, S. Selvaraj, R. Suganya, M. Kesavan, G. Serdaroglu, S. Gunasekaran, S. Kumaresan, Experimental and theoretical investigations on electronic struc- ture of 5-(hydroxymethyl)-2-furaldehyde: An antisickling agent identified from terminalia bellirica. Chemical Data Collections, 29, (2020) 100498, https://doi.org/10. 1016/j.cdc.2020.100498
- M.U. Hasan, M.F. Ali, A. Bukhari, Structural characterization of Saudi Arabian heavy crude oil by nmr spectroscopy, Fuel. 62(5), (1983) 518-523 https://doi.org/10.1016/0016-2361(83)90219-3
- Fiorella Meneghetti CCDC 1463711: Experimental Crystal Structure Determination, 2016, https://doi.org/10.5517/ccdc.csd.cc1l43hb
- A. Ram Kumar, S. Selvaraj, G. Sheeja Mol, M. Selvaraj, L. Ilavarasan, S.K. Pandey, P. Jayaprakash, S. Awasthi, O. Albormani, A. Ravi, Synthesis, solvent-solute interactions (polar and nonpolar), spectroscopic insights, topological aspects, Fukui functions, molecular docking, ADME, and donor-acceptor investigations of 2-(trifluoromethyl) benzimidazole: A promising candidate for antitumor pharmacotherapy. Journal of Molecular Liquids, 393, (2023) 123661. https://doi.org/10.1016/j.molliq.2023.123661.
- A. Ram Kumar, L. Ilavarasan, G. Sheeja Mol, S. Selvaraj, M. Azam, P. Jayaprakash, M. Kesavan, M. Alam, J. Dhanalakshmi, S.I. Al-Resayes, A. Ravi, Spectroscopic (FT-IR, FT-Raman, UV-Vis and NMR) and computational (DFT, MESP, NBO, NCI, LOL, ELF, RDG and QTAIM) profiling of 5-chloro-2-hydroxy-3-methoxybenzaldehyde: A promising antitumor agent. Journal of Molecular Structure, 1298, (2023) 136974, https://doi.org/10.1016/j.molstruc.2023.136974
- S. Selvaraj, Computational study on the structural features, vibrational aspects, chemical shifts, and electronic properties of 1, 4- Dinitrosopiperazine-2-carboxylic acid: Insights into donor-acceptor interactions and thermodynamic properties. International Research Journal of Multidisciplinary Technovation, 6(1), (2024) 1-16. https://doi.org/10.54392/irjmt2411
- P. Rajkumar, S. Selvaraj, P. Anthoniammal, A. Ram Kumar, K. Kasthuri, S. Kumaresan, S., 2023. Structural (monomer and dimer), spectroscopic (FT-IR, FT-Raman, UV–Vis and NMR) and solvent effect (polar and nonpolar) studies of 2 methoxy-4-vinyl phenol. Chemical Physics Impact, 7, (2023) 100257, https://doi.org/10.1016/j.chphi.2023.100257