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      Estrone-Based Derivatives Stabilize the c-MYC and c-KIT G-Quadruplex DNA Structures

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          Abstract

          G-rich sequences are present across the genome and can fold to form dynamic secondary structures, namely, G-quadruplexes (G4). These structures play a pivotal role in regulating numerous biological processes including replication, transcription, and translation. Therefore, targeting these structures using molecular scaffolds is an attractive approach to modulating their functions. Herein, we report the synthesis of three estrone-based derivatives ( Est-1, Est-2, and Est-3) with a nonplanar core and a cationic alkyl side chain as G4 stabilizers. CD melting and polymerase stop assay results indicate that these ligands preferentially stabilize parallel c-MYC and c-KIT1 G4s over the other G4s and duplex DNAs. The ligand Est-3 shows cytotoxicity against cancer cell lines and effectively downregulates the c-KIT gene in HepG2 cell lines. Molecular modeling and dynamics studies showed that the ligand prefers stacking over the 5′-quartet of c-MYC G4 using the aromatic ring of the ligand. Overall, the findings of this study demonstrate that even G4 ligands can accommodate nonplanar scaffolds, which opens up new avenues for ligand design.

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          Most cited references51

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          VMD: Visual molecular dynamics

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            AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

            We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.
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              Development and testing of a general amber force field.

              We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching. Copyright 2004 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                ACS Omega
                ACS Omega
                ao
                acsodf
                ACS Omega
                American Chemical Society
                2470-1343
                29 January 2024
                13 February 2024
                : 9
                : 6
                : 6616-6626
                Affiliations
                Department of Chemistry, Indian Institute of Technology Bombay , Powai, Mumbai 400076, India
                Author notes
                Author information
                https://orcid.org/0000-0001-9104-3708
                Article
                10.1021/acsomega.3c07574
                10870291
                38371752
                df77afa5-386f-41aa-97f7-63d86f2ad287
                © 2024 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 30 September 2023
                : 28 November 2023
                : 20 November 2023
                Funding
                Funded by: Department of Science and Technology, Ministry of Science and Technology, India, doi 10.13039/501100001409;
                Award ID: NA
                Funded by: Indian Institute of Technology Bombay, doi 10.13039/501100005808;
                Award ID: NA
                Funded by: Ministry of Education, India, doi 10.13039/501100004541;
                Award ID: NA
                Funded by: University Grants Committee, doi 10.13039/501100001839;
                Award ID: NA
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                Article
                Custom metadata
                ao3c07574
                ao3c07574

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