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Computational investigation of 4,5-diphenyl-1H-pyrrole-3-carboxylic acid derivatives as B-cell lymphoma-extra large (Bcl-xL) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

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Abstract

B-cell lymphoma-extra large (Bcl-xL) can inhibit apoptosis via heterodimerization with pro-apoptotic Bcl-2 family proteins, and is over-expressed in many different types of human tumors and has been regarded as a novel cancer therapeutic strategy. Due to the fact that current Bcl-xl inhibitors lack sustained effectiveness and the occurrence of some unpredictable side effects, the development of new inhibitors is necessary. In this study, computational study was applied to a series of Bcl-xL inhibitors to reveal the relationship between structure and activities through applying molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR), and molecular dynamic (MD) simulations. A molecular docking study was performed to explore possible modes of action between inhibitors and Bcl-xL protein. Subsequently, 3D-QSAR models were generated with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values were computed as 0.927 and 0.999, while those were computed as 0.943 and 0.998 for the best CoMSIA model. Twenty new Bcl-xL inhibitors were designed, and all their predictive activities were improved than molecules in the dataset based on the contour maps. In addition, MD simulations were conducted to evaluate the stability of the complexes conformed by two inhibitors and Bcl-xL, and the results were consistent with those of the molecular docking and 3D-QSAR studies. Finally, binding free energy was computed through molecular mechanics performed by surface area approach (MM-GBSA), and the result congruent with the activities which indicated van der Waals as well as lipophilic energy contributing the most during the molecular with Bcl-xL protein binding. In brief, our research provided valuable information for further development of Bcl-xL inhibitors.

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Abbreviations

Bcl-xL:

B-cell lymphoma-extra large

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity indices analysis

LOO:

Leave-one-out

MD:

Molecular dynamics

MM-GBSA:

Molecular Mechanics Generalized Born Surface Area

ONC:

The optimum number of component

PDB:

Protein data bank

PH:

Pleckstrin nomology

PLS:

Partial Least Squares

PTEN:

Phosphatase and tensin homolog

Q2 :

Cross-validated coefficient

R2 :

The correlation coefficient

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

SASA:

Solvent accessible surface area

SEE:

The standard error of estimate

SPC:

Simple point charge

XED:

Extended election distribution

3D-QSAR:

Three-dimensional quantitative structure-activity relationships

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Acknowledgments

This work was financially supported by LiaoNing Revitalization Talents Program (XLYC1807118), Shenyang Young Scientific and Technological Innovators Programme (RC200408), and Liaoning BaiQianWan Talents Program (2018).

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Authors and Affiliations

  1. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, People’s Republic of China

    Heng Zhang, Xi Gu, Churen Meng, Di Zhou, Gang Chen, Yang Liu & Ning Li

  2. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Jian Wang & Yang Liu

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  1. Heng Zhang
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  2. Xi Gu
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  3. Churen Meng
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  4. Di Zhou
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  7. Yang Liu
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Correspondence to Yang Liu or Ning Li.

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Zhang, H., Gu, X., Meng, C. et al. Computational investigation of 4,5-diphenyl-1H-pyrrole-3-carboxylic acid derivatives as B-cell lymphoma-extra large (Bcl-xL) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations. Struct Chem 32, 1005–1018 (2021). https://doi.org/10.1007/s11224-020-01631-8

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