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Structural based screening of potential inhibitors of SMAD4: a step towards personalized medicine for gall bladder and other associated cancers

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Abstract

Gall bladder cancer (GBC) is an aggressive and most common malignancy of biliary tract lacking effective treatment due to unavailability of suitable biomarkers and therapeutics. SMAD4 is an essential mediator of transforming growth factor-β pathway involved in various cellular processes like growth, differentiation and apoptosis and also recognized as therapeutic target for GBC and other gastrointestinal tract cancers. In the present study, 3D structure of SMAD4 mutants was optimized through molecular dynamics simulation (MDS) along with wildtype. Furthermore, binding site of protein was predicted through hybrid approach and structural based virtual screening against two drug libraries was performed followed by docking. MDS of top docking score protein–ligand complexes were carried, and binding free energy was rescored. Two potential inhibitors, namely ZINC2098840 and ZINC8789167, were screened that displayed higher binding affinity towards mutant proteins compared with wildtype and both hydrophilic as well as hydrophobic interactions play a crucial role during protein–ligand binding. Current study identified novel and potent inhibitors of SMAD4 mutant that could be used as a drug candidate for the development of personalized medicine for gall bladder and other associated cancers.

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Data availability

The datasets supporting the conclusion of this article are included within the article/supplementary material.

Abbreviations

GBC:

Gall bladder cancer

GROMACS:

Groningen machine for chemical simulation

MDS:

Molecular dynamics simulation

MMD:

Million molecular database

MMPBSA:

Molecular mechanics Poisson Boltzmann surface area

MT:

Mutant

NCD:

Natural compound database

PDB:

Protein data bank

Rg:

Radius of gyration

RMSD:

Root-mean-square deviation

RMSF:

Root-mean-square fluctuation

SAD:

SMAD4 activated domain

SMAD4:

Mothers against decapentaplegic homolog 4

SNP:

Single nucleotide polymorphism

SNV:

Single nucleotide variant

TGF-β:

Transforming growth factor-β

WT:

Wildtype

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Acknowledgement

Rakesh and Rahul thank Indian Council of Medical Research and University Grant Commission, respectively, for their research fellowships.

Funding

Indian Council of Medical Research, Grant/Award Number: 5/13/1/TF/2015/NCD-III.

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Authors and Affiliations

  1. Dr.B.R.A.-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India

    Rakesh Kumar, Rahul Kumar & Pranay Tanwar

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  1. Rakesh Kumar
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  2. Rahul Kumar
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  3. Pranay Tanwar
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Contributions

RK. and PT. conceptualized and designed the study. RK. and RK. performed the experiments. RK. analysed the data and wrote manuscript. PT. provided laboratory infrastructure. All authors read and approved the final version of manuscript.

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Correspondence to Pranay Tanwar.

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Kumar, R., Kumar, R. & Tanwar, P. Structural based screening of potential inhibitors of SMAD4: a step towards personalized medicine for gall bladder and other associated cancers. Mol Divers 25, 1945–1961 (2021). https://doi.org/10.1007/s11030-021-10210-w

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