Mohammad Kawsar Sharif Siam
ABSTRACT
Cancer has several pathways by which it is developed in our body. Among them folic acid biosynthetic pathway is one where dihydrofolate reductase (DHFR) enzyme converts dihydrofolate into tetrahydrofolate which leads to unwanted and uncontrollable growth of tissues. Our aim of this study is to design DHFR antagonistic potential small molecules that inhibits Folic Acid Biosynthetic Pathways. In this study, Human DHFR obtained from Protein Data Bank (PDB) docked with several established anticancer drugs including Afatinib, Doxorubicin, Trimetrexate, Curcumin & Trimethoprim and several potential small molecules including Acarbose, Adenosine monophosphate, Abacavir, Aceprometazine & Isoxyl; obtained from PubChem and Drug Bank respectively. PyMOL and PyRx were used to visualize, curate and dock. For validation purpose Discovery Studio and Ramachandran Plot were run. Results after docking showed best binding affinities of established anticancer drugs with Human DHFR throughout the generations for example Methotrexate to Trimethoprim. Potential small molecules which belong from different therapeutic classes.
- Berman, H.M. et al. 2014. The Protein Data Bank archive as an open data resource. Journal of Computer-Aided Molecular Design. 28, 10, 1009--1014.Google Scholar
Cross Ref
- Binkowski, T.A. et al. 2003. CASTp: Computed Atlas of Surface Topography of proteins. Nucleic Acids Research. 31, 13, 3352--3355.Google ScholarCross Ref
- Dallakyan, S. and Olson, A.J. 2015. Small-molecule library screening by docking with PyRx. Methods in Molecular Biology. 243--250.Google Scholar
- DeLano, W. 2002. PyMOL: An open-source molecular graphics tool. CCP4 Newsletter On Protein Crystallography. 700.Google Scholar
- Gangaraju Vamsi K. Lin Haifan 2009. Introduction to Cancer Chemotherapeutics. Nat Rev Mol Cell Biol.10 (2), 1, 116--125.Google Scholar
- Guex, N. and Peitsch, M.C. 1997. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis. 18, 15, 2714--2723.Google ScholarCross Ref
- Knox, C. et al. 2011. DrugBank 3.0: A comprehensive resource for "Omics" research on drugs. Nucleic Acids Research. 39, SUPPL. 1, 1035--1041.Google ScholarCross Ref
- Li, Q. et al. 2011. PubChem as a public resource for drug discovery. Drug Discov Today. 15, 23--24, 1052--1057.Google Scholar
- Lovell, S.C. et al. 2003. Structure validation by C alpha geometry: phi, psi and C beta deviation. Proteins-Structure Function and Genetics. 50, 437--450.Google ScholarCross Ref
- O'Boyle, N.M. et al. 2011. Open Babel: An Open chemical toolbox. Journal of Cheminformatics. 3, 10, 33.Google ScholarCross Ref
- Polshakov, V.I. 2001. Dihydrofolate reductase: Structural aspects of mechanisms of enzyme catalysis and inhibition. Russian Chemical Bulletin. 50, 10, 1733--1751.Google ScholarCross Ref
- Robinson, J. et al. 2013. IPD - The Immuno Polymorphism Database. Nucleic Acids Research. 41, D1, 1234--1240.Google ScholarCross Ref
- Sakchaisri, K. et al. 2017. Anticancer activity of a novel small molecule tubulin inhibitor STK899704. Plos One. 12, 3, 1--18.Google ScholarCross Ref
- Systems, D. 2017. Biovia discovery studio. COMPREHENSIVE MODELING AND SIMULATIONS FOR LIFE SCIENCESE BIOVIA DISCOVERY STUDIO 8, 2--5.Google Scholar
- Tamura, K. et al. 2013. MEGA6: Molecular evolutionary genetics analysis version 6.0. Molecular Biology and Evolution. 30, 12, 2725--2729.Google ScholarCross Ref
- Thurston, D.E. 2007. Chemistry and pharmacology of anticancer drugs. British journal of cancer. 97, 12, 1713.Google Scholar
- Trott, O. and Olson, A. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry. 31, 2, 455--461.Google Scholar
- Yu, J. et al. 2009. Roll: A new algorithm for the detection of protein pockets and cavities with a rolling probe sphere. Bioinformatics. 26, 1, 46--52. Google ScholarDigital Library
Index Terms
- In Silico Structure Based Designing of Dihydrofolate Reductase Enzyme Antagonists and Potential Small Molecules That Target DHFR Protein to Inhibit the Folic Acid Biosynthetic Pathways
Recommendations
The in silico identification of small molecules for protein-protein interaction inhibition in AKAP-LbcRhoA signaling complex
Display Omitted The A-Kinase Anchoring Protein, i.e. AKAP-Lbc is involved in cardiac repolarization by mediating Rho GTPases activation.The oncogenic AKAP-Lbc causes the RhoA GTPase hyperactivity based hypertrophic cardiomyocytes.The in silico drug ...
In silico identification of novel IL-1β inhibitors to target protein-protein interfaces
Display Omitted The study encompasses QSAR modeling, pharmacophore modeling and docking simulation.QSAR and pharmacophore modeling was performed for IL-1β inhibitors.The activity of 7 million compounds from ZINC database was predicted by QSAR model.The ...
A multidrug efflux protein in Mycobacterium tuberculosis; tap as a potential drug target for drug repurposing
AbstractTuberculosis (TB) is a serious communicative disease caused by Mycobacterium tuberculosis. Although there are vaccines and drugs available to treat the disease, they are not efficient, moreover, multidrug-resistant ...
Graphical abstractDisplay Omitted
Highlights- Tuberculosis (TB) is a serious communicative disease caused by M. tuberculosis.
Comments