Romanian Society of Pharmaceutical Sciences
 

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DESIGN, MOLECULAR DOCKING AND ADME STUDIES OF NEW NAPROXEN DERIVATIVES AS ESTROGEN RECEPTOR ANTAGONISTS

KANAR M. ALAWAD 1* ASMAA ADNAN ABDULNABI 1 JESSICA SHLIMOON HANNA 2 , , , TIBA M. HAMEED 1, KANY A. ABDULQADER 1, HUMAM L. QUSAY 3 , NOOR ALI HUSSEIN SABZI 4, ANWAR A. TAMER 5, HAWAZIN AZIZ HAMIM 6

1 Department of Pharmaceutical Chemistry, College of Pharmacy, AI-Nahrain University, Baghdad, Iraq
2 National Diabetes Center, Mustansiriyah University, Baghdad, Iraq
3 College of Pharmacy, Al-Farabi University, Baghdad, Iraq
4 Ministry of Health and Environments, Department of Health in Baghdad, Rusafa, Baghdad, Iraq
5 Department of Pharmaceutical Chemistry, College of Pharmacy/University of Baghdad, Baghdad, Iraq
6 Department of Pharmaceutical Chemistry, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

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The design of new anticancer agents aims to develop powerful treatments with fewer side effects. Using the Genetic Optimi- zation for Ligand Docking (GOLD) software, new naproxen-based compounds were designed and primarily screened for anti- cancer efficacy by interacting with the estrogen receptor, Protein Data Bank (PDB) code: 3ERT. The new derivatives can be synthesized by reacting naproxen with semicarbazide to form the intermediate (N) and then reacting the N with an aldehyde (Schiff base reaction) to produce the final compounds (N1A-N9A). To anticipate the pharmacokinetics of the designed com- pounds, computational approaches, including absorption, distribution, metabolism, and excretion (ADME) studies, were per- formed using the Swiss ADME server. In addition, all of the designed compounds met the rule of five for M.W., H-bond acceptor, and topological polar surface area (TPSA), but did not meet the H-bond donor and partition coefficient. Compounds (N9A, N4A) interacting with amino acids in the active pocket of docking studies of ligands with the ER-α protein (breast cancer protein) showed increased Piecewise Linear Potential (PLP) fitness values near the reference tamoxifen, suggesting potential activity. Throughout the simulation period, the molecule S2 exhibited stable fluctuations, with root-mean-square deviation (RMSD) values below 3 Å when modeled in the enzyme pocket.