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Identification of small molecule inhibitors against Lin28/let-7 to suppress tumor progression and its alleviation role in LIN28-dependent glucose metabolism

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Abstract

The reciprocal suppression of an RNA-binding protein LIN28 (human abnormal cell lineage 28) and miRNA Let-7 (Lethal 7) is considered to have a prime role in hepatocellular carcinoma (HCC). Though targeting this inhibition interaction is effective for therapeutics, it causes other unfavorable effects on glucose metabolism and increased insulin resistance. Hence, this study aims to identify small molecules targeting Lin28/let-7 interaction along with additional potency to improve insulin sensitivity. Of 22,14,996 small molecules screened by high throughput virtual screening, 6 molecules, namely 41354, 1558, 12437, 23837, 15710, and 8319 were able to block the LIN28 interaction with let-7 and increase the insulin sensitivity via interacting with PPARγ (peroxisome proliferator-activated receptors γ). MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) analysis is used to re-score the binding affinity of docked complexes. Upon further analysis, it is also seen that these molecules have superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties and form stable complexes with the targets for a significant period in a biologically simulated environment (Molecular Dynamics simulation) for 100 ns. From our results, we hypothesize that these identified 6 small molecules can be potential candidates for HCC treatment and the glucose metabolic disorder caused by the HCC treatment.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

2D:

Two-Dimensional

3D:

Three-Dimensional

ADME:

Absorption, Distribution, Metabolism and Excretion

B3LYP:

Backe’s three Lee-Yang-Parr

DFT:

Density Functional Theory

EMM:

Molecular Mechanics Energies

GNP:

Non-Polar solvation

GSGB:

SGB polar solvation model

H-bonds:

Hydrogen Bonds

HCC:

Hepatocellular carcinoma

HOMO:

Highest Occupied Molecular Orbital

HTVS:

High Throughput Virtual Screening

Let-7:

Lethal 7

LIN28:

Human abnormal cell lineage 28

LUMO:

Lowest Unoccupied Molecular Orbital

MD:

Molecular Dynamics simulation

MESP:

Molecular Electrostatic Potential

miRNA:

microRNA

MM-GBSA:

Molecular Mechanics-Generalized Born Surface Area

NPT:

Isothermal–isobaric ensemble

OPLS:

Optimized Potential for Liquid Simulation

OPLS-AA:

Optimized Potential for Liquid Simulation- All Atom

PPARγ:

Peroxisome Proliferator-Activated Receptorsγ

PBF:

Poisson Boltzmann Finite

QPlogS:

Aqueous solubility

QPPCaco :

Caco-2 cell permeability

QPlogHERG:

IC50 value for blockage of HERG K+ channels

QPlogPo/w:

Octanol/water partition coefficient

RMSF:

Root Mean-Square Fluctuation

RMSD:

Root Mean-Square Deviation

RNA:

Ribonucleic Acid

SP:

Standard Precision

SPC:

Simple Point Charge

SD:

Standard Deviation

XP:

Extra Precision

ZKD:

Zinc Knuckle Domain

PCA:

Principal Component Analysis

FEL:

Free Energy Landscape

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Centre for Excellence in Nanobio Translational Research, Department of Pharmaceutical Technology, University College of Engineering, Anna University (BIT Campus), Tiruchirappalli, Tamil Nadu, India

    Rachanaa Raja & Ruckmani Kandasamy

  2. Centre for Drug Discovery, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India

    Rajamanikandan Sundararaj

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  1. Rachanaa Raja
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All the authors contributed to the study conception, idea generation, methodology design, results generation and analysis. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ruckmani Kandasamy.

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Raja, R., Sundararaj, R. & Kandasamy, R. Identification of small molecule inhibitors against Lin28/let-7 to suppress tumor progression and its alleviation role in LIN28-dependent glucose metabolism. Med Oncol 41, 118 (2024). https://doi.org/10.1007/s12032-024-02350-4

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