Discovering novel multi-target

:Title

Discovering novel multi-target compounds against aspartyl viral polymerases via ligand-based pharmacophore and structure-based screening

Authors:

Armin Zarei, Mohammad Ezati, Marc T. Morris, Gerhard Schenk, Hadi Adibi

Journal: Scientific Reports

Year: 2026

 Abstract:

Viral polymerases are key targets for antiviral drug development due to their crucial role in viral replication. This study seeks to discover novel inhibitors using virtual screening of a 200,583-member ZINC-based library, targeting three aspartyl-based viral polymerases: SARS-CoV-2 RdRp, HIV-1 RT, and HCV NS5B. In this line, applying RO5, drug-likeness, and PAINS filters, leading to a pharmacophore model with Ribavirin as the benchmark. Four ligands (Ligands 1-4) with the highest binding affinities were identified via molecular docking and ADME/T studies. These candidates were then subjected to 200 ns molecular dynamics (MD) simulations and binding free-energy calculations to evaluate binding stability. The computational analyses demonstrated that all four ligands stably bound the polymerase active sites and induced some conformational changes. According to MM/PBSA results, Lig-2 and Lig-1 surpass Ribavirin in SARS-CoV-2 RdRp and HIV-1 RT complexes, while Ribavirin showed the strongest binding in HCV NS5B. ADME/T studies supported the pharmacological potential of the ligands, with Lig-2 emerging as a promising lead against all targets, and Lig-1, Lig-3, and Lig-4 showing potential for multi-target antiviral development.    

Exploring DNA-targeted cytotoxic mechanisms of Novel N-Phenyl pyridopyrimidine

:Title

Exploring DNA-targeted cytotoxic mechanisms of Novel N-Phenyl pyridopyrimidine analogs through experimental and computational studies
:Authors

Parisa Pourgoodarzi, Armin Zarei, Leila Hosseinzadeh, Seyyed Abolghasem Ghadami, Zahra Samadi, Fereshteh Jalilian, Hadi Adibi
Journal: Journal of Molecular Structure
Year: 2026
:Abstract
Over the last two decades, pyridopyrimidine analogs have captivated many enthusiasts due to their potent anticancer potential. Bearing this in mind, in this study, a novel series of N-phenyl pyridopyrimidine analogs (L1-L18) were generated and characterized via FT-IR, 1H-NMR, 13C-NMR, MASS, and elemental analysis. The N-phenyl pyridopyrimidine analogs were then introduced to in vitro studies to assess their cytotoxicity potential against prostate cancer (PC3), cervical cancer (HeLa) cell lines, breast cancer (MCF7), as well as on normal fibroblast cells, demonstrating that the third (six out of thirteen) of the synthetic ligands had higher selectivity against PC3 cell lines. Also, compound L17 selectively targeted cancer cell lines, and showing the most anticancer potential with IC50 magnitudes of 14.01 μM, 12.5 μM, and 45 μM, respectively. SAR results also indicated that the para-substituted compounds enhanced PC3 selectivity, and the presence of -N(Me)2 moiety in this position (like L17) showed the strongest cytotoxicity and no fibroblast inhibition, making it a promising therapeutic candidate with high selectivity. Interestingly, docking results showed that the para-substituted ligands (L3, L6, L9, L14, and L17) showed the lowest binding energies with DNA and bound to DNA minor groove by polar interactions. Then, L3 and L17 were chosen for 100 ns molecular dynamics simulations. MD simulations confirmed stable DNA binding for L17 and L3, with L17 inducing greater structural instability. L17 showed the strongest binding energy (-126.5 kJ/mol), mainly governed by Van der Waals forces, aligning with docking results. To sum, compound L17 as a promising anticancer agent is nominated for further studies to prove its efficacy.

Synthesis, characterization, cytotoxic investigation of curcumin-based 4-phenylchromene derivatives and study of DNA interaction using experimental and computational methods

:Title
Synthesis, characterization, cytotoxic investigation of curcumin-based 4-phenylchromene derivatives and study of DNA interaction using experimental and computational methods

Authors:

Fereshteh Jalilian, Sajad Moradi, Leila Hosseinzadeh, Armin Zarei, Pouya Raeisi, Mohsen Shahlaei, Komail Sadrjavadi, Hadi Adibi

Journal: Journal of Molecular Liquids

Year: 2025

:Abstract

Curcumin exhibits a distinctive anti-proliferative effect on various malignant tumors. However, its limitations, such as low bioavailability and poor aqueous solubility, have led to the development of different curcumin analogs. In this study, thirteen curcumin-based 4-phenylchromene compounds were synthesized as ligands through nucleophilic additions involving curcumin, 3-dimethylaminophenol, and various aryl aldehydes. The structures of these synthesized compounds were verified using FT-IR, ¹H NMR, ¹³C NMR, and MASS spectral data. Their cytotoxic effects were assessed using the MTT assay on A2780 (ovarian cancer) and HeLa (cervical cancer) cell lines. Additionally, FT-IR, fluorescence, UV-vis spectroscopy, and molecular modeling studies were conducted to investigate the interaction between selected ligands and calf-thymus DNA. Among the compounds, L3 emerged as the most toxic ligand, with an IC50 ranging from 4 to 4.5 µg/mL, and was found to bind to CT-DNA in a groove-binding mode with a binding constant of 3.98 × 10³ M⁻¹.