Molecular Docking Insights of Newly Synthesized Schiff Base Monomers and Evaluating the Anticancer Activity of Their Polymers

Abstract

Introduction The molecular docking technique has shown efficacy with small molecules but faces challenges when applied to macromolecules. To overcome this limitation, a focused approach targeting the active repeat units (monomers) of macromolecules was adopted. This study synthesized ten new dihydroxy Schiff base monomers (SBM1-SBM10) featuring azo moieties and alkoxy side groups. These were attached to human 3-alpha-hydroxysteroid dehydrogenase type 3 (4XO6), a protein linked to breast cancer, using molecular docking via the AutoDock tool.

Materials and Methods The synthesis of dihydroxy Schiff base monomers SBM1-SBM10 with azo moieties and alkoxy side groups was carried out. These synthesized monomers were then docked with human 3-alpha-hydroxysteroid dehydrogenase type 3 (4XO6) utilizing AutoDock. Among these, the most promisingly docked monomer, SBM8, was selected for further experimentation. SBM8 was polymerized with terephthaloyl chloride to produce a novel polyester termed PolySyringaldehydeDiaminodiphenylSulfone (PSDS). The anticancer activity of PSDS was assessed using the MCF7 human breast cancer cell line. Concurrently, its cytotoxicity was evaluated via the MTT assay employing a normal VERO cell line.

Results The molecular docking analysis revealed the best-docked monomer, SBM8, which was subsequently used for the synthesis of PSDS. The newly formed polyester, PSDS, demonstrated significant anticancer properties against the MCF7 human breast cancer cell line. Simultaneously, the cytotoxicity evaluation on the normal VERO cell line indicated a favorable safety profile for PSDS.

Conclusion The study's findings highlight the successful synthesis and docking of dihydroxy Schiff base monomers with 4XO6, resulting in the creation of PSDS. This newly synthesized polyester, PSDS, exhibited promising anticancer activity against the MCF7 cell line while demonstrating minimal cytotoxicity towards normal VERO cells. These results suggest the potential of PSDS as a targeted therapeutic agent against breast cancer, warranting further investigation and development.

Keywords

docking - monomers - anticancer activity - polymers - breast cancer

• References

• 1 Taylor RD, Jewsbury PJ, Essex JW. A review of protein-small molecule docking methods. J Comput Aided Mol Des 2002; 16 (03) 151-166
• 2 Ewing TJA, Makino S, Skillman AG, Kuntz ID. DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des 2001; 15 (05) 411-428
• 3 Mac Kerell AD. Developments in the CHARMM all-atom empirical energy function for biological molecules. Am Chem Soc 1998; 216: U696
• 4 Pearlman DA, Case DA, Caldwell JW. et al. AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 1995; 91 (1–3): 1-41
• 5 Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 1996; 118 (45) 11225-11236
• 6 Comşa Ş, Cîmpean AM, Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer Res 2015; 35 (06) 3147-3154
• 7 Khuhawar MY, Mughal MA, Channar AH. Synthesis and characterization of some new Schiff base polymers. Eur Polym J 2004; 40 (04) 805-809
• 8 Salmaso V. Exploring Protein Flexibility during Docking to Investigate Ligand-Target Recognition [PhD Thesis]. Padova, Italy: University of Padova; 2018
• 9 Taylor RD, Jewsbury PJ, Essex JW. A review of protein-small molecule docking methods. J Comput Aided Mol Des 2002; 16 (03) 151-166
• 10 Gohlke H, Klebe G. Statistical potentials and scoring functions applied to protein-ligand binding. Curr Opin Struct Biol 2001; 11 (02) 231-235
• 11 Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Computeraided Drug Des 2011; 7 (02) 146-157
• 12 Mohammed Ibrahim A, Shabeer TK. Synthesis and characterization of nanoclay doped PVC/polyester composite film. J Indian Chem Soc 2019; 96: 9-13
• 13 Zhang B, Hu XJ, Wang XQ. et al. Human 3α-hydroxysteroid dehydrogenase type 3: structural clues of 5α-DHT reverse binding and enzyme down-regulation decreasing MCF7 cell growth. Biochem J 2016; 473 (08) 1037-1046
• 14 Ortmann J, Prifti S, Bohlmann MK, Rehberger-Schneider S, Strowitzki T, Rabe T. Testosterone and 5 α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines. Gynecol Endocrinol 2002; 16 (02) 113-120
• 15 Chua VYL, Larma I, Harvey J, Thomas MA, Bentel JM. Activity of ABCG2 is regulated by its Expression and localization in DHT and cyclopamine-treated breast cancer cells. J Cell Biochem 2016; 117 (10) 2249-2259