Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer

被引:11
作者
Saeed, Amna [1 ]
Ejaz, Syeda Abida [1 ]
Sarfraz, Muhammad [2 ]
Tamam, Nissren [3 ]
Siddique, Farhan [4 ,5 ]
Riaz, Naheed [6 ]
Abul Qais, Faizan [7 ]
Chtita, Samir [8 ]
Iqbal, Jamshed [9 ]
机构
[1] Islamia Univ Bahawalpur, Fac Pharm, Dept Pharmaceut Chem, Bahawalpur 63100, Pakistan
[2] Al Ain Univ, Coll Pharm, Al Ain Campus,POB 64141, Al Ain, U Arab Emirates
[3] Princess Nourah bint Abdulrahman Univ, Coll Sci, Dept Phys, POB 84428, Riyadh 11671, Saudi Arabia
[4] Linkoping Univ, Dept Sci & Technol, Lab Organ Elect, SE-60174 Norrkoping, Sweden
[5] Royal Inst Med Sci RIMS, Dept Pharm, Multan 60000, Pakistan
[6] Islamia Univ Bahawalpur, Dept Chem, Baghdad Ul Jadeed Campus, Bahawalpur 63100, Pakistan
[7] Aligarh Muslim Univ, Fac Agr Sci, Dept Agr Microbiol, Aligarh 202002, Uttar Pradesh, India
[8] Hassan II Univ Casablanca, Fac Sci Ben MSik, Lab Analyt & Mol Chem, BP7955, Casablanca, Morocco
[9] COMSATS Univ Islamabad, Ctr Adv Drug Res, Abbottabad Campus, Abbotabad 22060, Pakistan
来源
MOLECULES | 2022年 / 27卷 / 13期
关键词
aldose reductase; molecular docking; density functional theory; ADMET properties; AutoDock tools; Molecular Operating Environment; SURVIVAL; GROMACS; AGENTS; DRUGS;
D O I
10.3390/molecules27133981
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
Both members of the aldo-keto reductases (AKRs) family, AKR1B1 and AKR1B10, are over-expressed in various type of cancer, making them potential targets for inflammation-mediated cancers such as colon, lung, breast, and prostate cancers. This is the first comprehensive study which focused on the identification of phenylcarbamoylazinane-1, 2,4-triazole amides (7a-o) as the inhibitors of aldo-keto reductases (AKR1B1, AKR1B10) via detailed computational analysis. Firstly, the stability and reactivity of compounds were determined by using the Guassian09 programme in which the density functional theory (DFT) calculations were performed by using the B3LYP/SVP level. Among all the derivatives, the 7d, 7e, 7f, 7h, 7j, 7k, and 7m were found chemically reactive. Then the binding interactions of the optimized compounds within the active pocket of the selected targets were carried out by using molecular docking software: AutoDock tools and Molecular operation environment (MOE) software, and during analysis, the Autodock (academic software) results were found to be reproducible, suggesting this software is best over the MOE (commercial software). The results were found in correlation with the DFT results, suggesting 7d as the best inhibitor of AKR1B1 with the energy value of -49.40 kJ/mol and 7f as the best inhibitor of AKR1B10 with the energy value of -52.84 kJ/mol. The other potent compounds also showed comparable binding energies. The best inhibitors of both targets were validated by the molecular dynamics simulation studies where the root mean square value of <2 along with the other physicochemical properties, hydrogen bond interactions, and binding energies were observed. Furthermore, the anticancer potential of the potent compounds was confirmed by cell viability (MTT) assay. The studied compounds fall into the category of drug-like properties and also supported by physicochemical and pharmacological ADMET properties. It can be suggested that the further synthesis of derivatives of 7d and 7f may lead to the potential drug-like molecules for the treatment of colon cancer associated with the aberrant expression of either AKR1B1 or AKR1B10 and other associated malignancies.
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页数:22
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