Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

被引：34

作者：

Elkaeed, Eslam B. ^{[1
]}

Yousef, Reda G. ^{[2
]}

Khalifa, Mohamed M. ^{[2
]}

Ibrahim, Albaraa ^{[2
]}

Mehany, Ahmed B. M. ^{[3
]}

Gobaara, Ibraheem M. M. ^{[3
]}

Alsfouk, Bshra A. ^{[4
]}

Eldehna, Wagdy M. ^{[5
,6
]}

Metwaly, Ahmed M. ^{[7
,8
]}

Eissa, Ibrahim H. ^{[2
]}

El-Zahabi, Mohamed Ayman ^{[2
]}

机构：

[1] AlMaarefa Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh 13713, Saudi Arabia

[2] Al Azhar Univ, Fac Pharm Boys, Pharmaceut Med Chem & Drug Design Dept, Cairo 11884, Egypt

[3] Al Azhar Univ, Fac Sci Boys, Zool Dept, Cairo 11884, Egypt

[4] Princess Nourah Bint Abdulrahman Univ, Coll Pharm, Dept Pharmaceut Sci, POB 84428, Riyadh 11671, Saudi Arabia

[5] Kafrelsheikh Univ, Fac Pharm, Dept Pharmaceut Chem, Kafrelsheikh 33516, Egypt

[6] Bach Univ Cairo, Sch Biotechnol, Bach City 11829, Egypt

[7] Al Azhar Univ, Fac Pharm Boys, Pharmacognosy & Med Plants Dept, Cairo 11884, Egypt

[8] City Sci Res & Technol Applicat SRTA City, Genet Engn & Biotechnol Res Inst, Biopharmaceut Prod Res Dept, Alexandria 21934, Egypt

来源：

MOLECULES | 2022年 / 27卷 / 19期

关键词：

apoptosis; anti-proliferative; immunomodulation; MD simulations; nicotinamide; VEGFR-2; inhibitors; BIOLOGICAL EVALUATION; MOLECULAR-DYNAMICS; ANTICANCER AGENTS; DERIVATIVES; APOPTOSIS; TOXICITY; CHARMM; ADMET; GUI;

D O I：

10.3390/molecules27196203

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC(50) values of 9.3 +/- 0.02 and 7.8 +/- 0.025 mu M against HCT-116 and HepG-2 cells, respectively, and IC50 of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-alpha and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.

引用

页数：19

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