Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques

被引:17
作者
Tabti, Kamal [1 ]
Baammi, Soukayna [2 ]
Sbai, Abdelouahid [1 ]
Maghat, Hamid [1 ]
Lakhlifi, Tahar [1 ]
Bouachrine, Mohammed [1 ,3 ]
机构
[1] Moulay Ismail Univ, Fac Sci, Mol Chem & Nat Subst Lab, Meknes, Morocco
[2] Mohammed VI Polytech Univ, African Genome Ctr AGC, Benguerir, Morocco
[3] Sultan Moulay Sliman Univ, High Sch Technol Khenifra, Benimellal, Morocco
关键词
Mcl-1; QSAR; HQSAR; docking molecular; MD simulation; MMPBSA; ADMET PREDICTION; DRUG DISCOVERY; BCL-2; PROTEINS; MCL-1; IDENTIFICATION; APOPTOSIS; SPECTRUM; DESIGN; CANCER; COMFA;
D O I
10.1080/07391102.2023.2183032
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
A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA (Q(2) = 0.689; R = 0.999; R-pred(2) = 0.986), CoMSIA (Q(2) = 0.614; R-2 = 0.923; R-pred(2) = 0.815) and HQSAR (Q(2)= 0.603; R-2 = 0.662; R-pred(2) = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC(50) inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma
引用
收藏
页码:13798 / 13814
页数:17
相关论文
共 50 条
[41]   3D-QSAR study, docking molecular and simulation dynamic on series of benzimidazole derivatives as anti-cancer agents [J].
El Mchichi, L. ;
Tabti, K. ;
Kasmi, R. ;
El-Mernissi, R. ;
El Aissouq, A. ;
En-nahli, F. ;
Belhassan, A. ;
Lakhlifi, T. ;
Bouachrine, M. .
JOURNAL OF THE INDIAN CHEMICAL SOCIETY, 2022, 99 (09)
[42]   Pharmacophore modeling, 3D-QSAR, and molecular docking study on naphthyridine derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1 [J].
Kirubakaran, Palani ;
Muthusamy, Karthikeyan ;
Singh, Kh Dhanachandra ;
Nagamani, Selvaraman .
MEDICINAL CHEMISTRY RESEARCH, 2013, 22 (08) :3812-3822
[43]   2/3D-QSAR, molecular docking and MD simulation studies of FtsZ protein targeting benzimidazoles derivatives [J].
Ahamad, Shahzaib ;
Islam, Asimul ;
Ahmad, Faizan ;
Dwivedi, Neeraj ;
Hassan, Md. Imtaiyaz .
COMPUTATIONAL BIOLOGY AND CHEMISTRY, 2019, 78 :398-413
[44]   Designing of novel ERRγ inverse agonists by molecular modeling studies of docking and 3D-QSAR on hydroxytamoxifen derivatives [J].
Li, Rui ;
Du, Yongli ;
Shen, Jingkang .
MEDICINAL CHEMISTRY RESEARCH, 2019, 28 (10) :1661-1673
[45]   Molecular modeling study on Mer kinase inhibitors using 3D-QSAR and docking approaches [J].
Anand Balupuri ;
Pavithra K. Balasubramanian ;
Seung Joo Cho .
Medicinal Chemistry Research, 2015, 24 :3730-3742
[46]   Design of Novel Thiazole-based Schiff Analogs as α-Amylase Inhibitors Using 3D-QSAR, ADME-Tox, Molecular Docking, Molecular Dynamics, Biological Efficacy, and Retrosynthesis [J].
Naanaai, Lhoucine ;
Ouabane, Mohamed ;
Moukhliss, Youness ;
El Aissouq, Abdellah ;
Zaitan, Hicham ;
Bouachrine, Mohammed ;
Khalil, Fouad .
CHEMISTRYSELECT, 2024, 9 (47)
[47]   Development of pyrrolidine and isoindoline derivatives as new DPP8 inhibitors using a combination of 3D-QSAR technique, pharmacophore modeling, docking studies, and molecular dynamics simulations [J].
Kaviani, Bita ;
Samani, Mojtaba Asad ;
Haghshenas, Hamed ;
Dehkordi, Marzieh Ghani .
MOLECULAR SIMULATION, 2023, 49 (01) :85-98
[48]   Molecular Modeling Studies on Benzimidazole Carboxamide Derivatives as PARP-1 Inhibitors Using 3D-QSAR and Docking [J].
Zeng, Huahui ;
Zhang, Huabei ;
Jang, Fubin ;
Zhao, Lingzhou ;
Zhang, Jianyuan .
CHEMICAL BIOLOGY & DRUG DESIGN, 2011, 78 (03) :333-352
[49]   Computational investigation of novel pyrimidine derivatives as potent FAK inhibitors via 3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis [J].
El Bahi, Salma ;
Boutalaka, Meryem ;
El Alaouy, Moulay Ahfid ;
Bouamrane, Soukaina ;
Alaqarbeh, Marwa ;
Choukrad, M'barek ;
Sbai, Abdelouahid ;
Bouachrine, Mohammed ;
Lakhlifi, Tahar .
NEW JOURNAL OF CHEMISTRY, 2023, 47 (27) :12816-12829
[50]   Discovery of small molecule inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulation and experimental validation against myeloid cell leukemia-1 (Mcl-1) [J].
Suleiman, Muhammad R. ;
Wang, Hanxun ;
Huang, Danxia ;
Wang, Huibin ;
Joseph, Johnson ;
Huang, Tianci ;
Zhang, Fengjiao ;
Wang, Jian ;
Cheng, Maosheng .
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2021, 39 (07) :2512-2525