*Article* **The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1***H***-Indole Derivative: In Silico and In Vitro Approaches**

**Eslam B. Elkaeed <sup>1</sup> , Reda G. Yousef <sup>2</sup> , Hazem Elkady <sup>2</sup> , Ibraheem M. M. Gobaara 3, Aisha A. Alsfouk <sup>4</sup> , Dalal Z. Husein <sup>5</sup> , Ibrahim M. Ibrahim 6, Ahmed M. Metwaly 7,8,\* and Ibrahim H. Eissa 2,\***


**Abstract:** Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1*H*indole derivative (compound **7**) was designed. The inhibitory potential of the designed compound was revealed via a molecular docking study that showed the appropriate binding. Then, MD simulation (six studies) over a period of 100 ns was performed to confirm the precise binding and optimum energy. Additionally, MM-GBSA reaffirmed the perfect binding, exhibiting a total precise energy of −40.38 Kcal/Mol. The MM-GBSA experiments named the essential amino acids in the protein–ligand interaction, employing the binding energy decomposition and revealing the diversity of interactions of compound **7** inside the VEGFR-2 enzyme. As compound **7** is new, DFT experiments were utilized for molecular structure optimization. Additionally, the DFT results validated the coherent interaction of compound **7** with the VEGFR-2 enzyme. A good value of drug-likeness of compound **7** was acknowledged via in silico ADMET studies. Interestingly, the experimental in vitro prohibitory potential of compound **7** was better than that of sorafenib, demonstrating an IC50 value of 25 nM. Notably, the strong inhibitory effects of compound **10** against two cancer cell lines (MCF-7 and HCT 116) were established with IC50 values of 12.93 and 11.52 μM, disclosing high selectivity indexes of 6.7 and 7.5, respectively.

**Keywords:** 1*H*-indole; VEGFR-2 inhibitors; molecular docking; MD simulations; MM-GBSA; PLIP; DFT; ADMET; in vitro antiproliferative
