# Design and Evaluation of New 6-Trifluoromethoxy-Isatin Derivatives as Potential CDK2 Inhibitors

## TL;DR

This study designs and evaluates new isatin compounds with a trifluoromethoxy group as potential CDK2 inhibitors for cancer treatment.

## Contribution

The paper introduces novel 6-trifluoromethoxy-isatin derivatives and evaluates their CDK2 inhibition potential using in silico methods.

## Key findings

- The derivatives form stable complexes with CDK2 through hydrogen bonds and hydrophobic interactions.
- The trifluoromethoxy group enhances ligand orientation and insertion into the CDK2 hydrophobic pocket.
- ADMET analysis shows favorable absorption and toxicity profiles with moderate solubility issues.

## Abstract

Cyclin-dependent kinase 2 (CDK2) plays a central role in cell cycle regulation and represents an important molecular target in anticancer drug development. In this study, a series of novel isatin derivatives substituted with a trifluoromethoxy group at the C6 position were designed and evaluated as potential CDK2 inhibitors using a comprehensive in silico approach. Density functional theory calculations were applied to analyze the electronic properties of the proposed compounds. Molecular docking and molecular dynamics simulations were used to investigate binding modes, conformational stability, and key interactions within the CDK2 active site. Binding free energies were estimated using the Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) method, while QSAR-based (Quantitative Structure–Activity Relationship) ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses were performed to assess drug-likeness and pharmacokinetic profiles. The results indicate that the investigated derivatives form stable complexes with CDK2, supported by persistent hydrogen bonds in the hinge region and favorable hydrophobic interactions. The trifluoromethoxy substituent significantly affects ligand orientation and promotes deeper insertion into the hydrophobic pocket compared with previously studied isatin analogues. ADMET predictions suggest generally favorable absorption and toxicity profiles, with moderate solubility limitations. Overall, these findings support the potential of 6-trifluoromethoxy-isatin derivatives as promising CDK2 inhibitors and provide a basis for further experimental studies.