Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Discovery, Design, and Development of Effective and Stable Binding Compounds for Mutant EGFR Inhibition

Author(s): Kshipra S. Karnik, Aniket P. Sarkate, Vaishanavi S. Jambhorkar and Pravin S. Wakte*

Volume 20, Issue 12, 2023

Published on: 03 September, 2022

Page: [1970 - 1981] Pages: 12

DOI: 10.2174/1570180819666220613094708

Price: $65

Abstract

Background: The epidermal growth factor receptor of the tyrosine kinase family has been largely targeted in mutations associated with non-small cell lung cancer. EGFR inhibitors have been produced that bind allosterically to the C797S mutant EGFR enzyme.

Objective: Here, the Waterswap tool has been used for the interpretation and visualization of trajectories of mutant EGFR-ligand complexes. Virtual screening of the generated compounds has been carried out along with its molecular docking and ADMET analysis.

Methods: Out of the generated library of compounds, the top 15 have been selected. Waterswap calculated the binding free energies of the compounds and thermodynamic properties of the enumerated compounds were compared with that of standard EAI045.

Results: It was observed that compound KSK-1 stabilized better than EAI045.

Conclusion: Waterswap analysis offers a promising new path in the hunt for improved tools for analyzing and visualizing molecular driving forces in protein-ligand complex simulations.

Keywords: EGFR, Waterswap, virtual screening, molecular docking, ADMET, styrylquinoline.

« Previous Next »
Graphical Abstract

[1]
Hoelder, S.; Clarke, P.A.; Workman, P. Discovery of small molecule cancer drugs: Successes, challenges and opportunities. Mol. Oncol., 2012, 6(2), 155-176.
[http://dx.doi.org/10.1016/j.molonc.2012.02.004] [PMID: 22440008]
[2]
Dayyani, F.; Gallick, G.E.; Logothetis, C.J.; Corn, P.G. Novel therapies for metastatic castrate-resistant prostate cancer. J. Natl. Cancer Inst., 2011, 103(22), 1665-1675.
[http://dx.doi.org/10.1093/jnci/djr362] [PMID: 21917607]
[3]
You, W.K.; Sennino, B.; Williamson, C.W.; Falcón, B.; Hashizume, H.; Yao, L.C.; Aftab, D.T.; McDonald, D.M. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res., 2011, 71(14), 4758-4768.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2527] [PMID: 21613405]
[4]
Wieduwilt, M.J.; Moasser, M.M. The epidermal growth factor receptor family: Biology driving targeted therapeutics. Cell. Mol. Life Sci., 2008, 65(10), 1566-1584.
[http://dx.doi.org/10.1007/s00018-008-7440-8] [PMID: 18259690]
[5]
Sharma, S.V.; Bell, D.W.; Settleman, J.; Haber, D.A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer, 2007, 7(3), 169-181.
[http://dx.doi.org/10.1038/nrc2088] [PMID: 17318210]
[6]
Santhi, M.P.; Bupesh, G.; Senthil Kumar, V.; Meenakumari, K.; Prabhu, K.; Sugunthan, S.; Manikandan, E.; Saravanan, K. Anticancer activity and drug likeliness of quinoline through in silico docking against cervical and liver cancer receptors. Indian J. Med. Res. Pharm, 2016, 3, 83-93.
[7]
Mason, J.S.; Bortolato, A.; Weiss, D.R.; Deflorian, F.; Tehan, B.; Marshall, F.H. High end GPCR design: Crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacol., 2013, 1(1), 23-46.
[http://dx.doi.org/10.1186/2193-9616-1-23]
[8]
Bodnarchuk, M.S. Water, water, everywhere… It’s time to stop and think. Drug Discov, 2016, 21(7), 1139-1146.
[http://dx.doi.org/10.1016/j.drudis.2016.05.009] [PMID: 27210724]
[9]
Graves, A.P.; Wall, I.D.; Edge, C.M.; Woolven, J.M.; Cui, G.; Le Gall, A.; Hong, X.; Raha, K.; Manas, E.S. A perspective on water site prediction methods for structure based drug design. Curr. Top. Med. Chem., 2017, 17(23), 2599-2616.
[http://dx.doi.org/10.2174/1568026617666170427095035] [PMID: 28460610]
[10]
Snyder, P.W.; Lockett, M.R.; Moustakas, D.T.; Whitesides, G.M. Is it the shape of the cavity, or the shape of the water in the cavity? Eur. Phys. J. Spec. Top., 2014, 223(5), 853-891.
[http://dx.doi.org/10.1140/epjst/e2013-01818-y]
[11]
Lu, Y.; Wang, R.; Yang, C.Y.; Wang, S. Analysis of ligand-bound water molecules in high-resolution crystal structures of protein-ligand complexes. J. Chem. Inf. Model., 2007, 47(2), 668-675.
[http://dx.doi.org/10.1021/ci6003527] [PMID: 17266298]
[12]
García-Sosa, A.T. Hydration properties of ligands and drugs in protein binding sites: tightly-bound, bridging water molecules and their effects and consequences on molecular design strategies. J. Chem. Inf. Model., 2013, 53(6), 1388-1405.
[http://dx.doi.org/10.1021/ci3005786] [PMID: 23662606]
[13]
Michel, J.; Tirado-Rives, J.; Jorgensen, W.L. Energetics of displacing water molecules from protein binding sites: Consequences for ligand optimization. J. Am. Chem. Soc., 2009, 131(42), 15403-15411.
[http://dx.doi.org/10.1021/ja906058w] [PMID: 19778066]
[14]
Krimmer, S.G.; Cramer, J.; Betz, M.; Fridh, V.; Karlsson, R.; Heine, A.; Klebe, G. Rational design of thermodynamic and kinetic binding profiles by optimizing surface water networks coating protein-bound ligands. J. Med. Chem., 2016, 59(23), 10530-10548.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00998] [PMID: 27933956]
[15]
Snyder, P.W.; Mecinovic, J.; Moustakas, D.T.; Thomas, S.W., III; Harder, M.; Mack, E.T.; Lockett, M.R.; Héroux, A.; Sherman, W.; Whitesides, G.M. Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase. Proc. Natl. Acad. Sci. USA, 2011, 108(44), 17889-17894.
[http://dx.doi.org/10.1073/pnas.1114107108] [PMID: 22011572]
[16]
Biswal, J.; Jayaprakash, P.; Rayala, S.K.; Venkatraman, G.; Rangaswamy, R.; Jeyaraman, J. WaterMap and molecular dynamic simulation-guided discovery of potential PAK1 inhibitors using repurposing approaches. ACS Omega, 2021, 6(41), 26829-26845.
[http://dx.doi.org/10.1021/acsomega.1c02032] [PMID: 34693105]
[17]
Sobhia, M.E.; Kumar, G.S.; Sivangula, S.; Ghosh, K.; Singh, H.; Haokip, T.; Gibson, J. Rapid structure-based identification of potential SARS-CoV-2 main protease inhibitors. Future Med. Chem., 2021, 13(17), 1435-1450.
[http://dx.doi.org/10.4155/fmc-2020-0264] [PMID: 34169728]
[18]
Manasa, B.; Manandhar, S.; Gangadhar, H.; Keerthi, P.; Kumar, H.B.; Ranganath Pai, K.S. Virtual structure-based docking, watermap, and molecular dynamics guided identification of the potential natural compounds as inhibitors of protein-tyrosine phosphatase 1B. J. Mol. Struct., 2021, 1226, 129396-129405.
[http://dx.doi.org/10.1016/j.molstruc.2020.129396]
[19]
Targowska-Duda, K.M.; Maj, M.; Drączkowski, P.; Budzyńska, B.; Boguszewska-Czubara, A.; Wróbel, T.M.; Laitinen, T.; Kaczmar, P.; Poso, A.; Kaczor, A.A. WaterMap-guided structure-based virtual screening for Acetylcholinesterase inhibitors. ChemMedChem, 2022, 17(8), e202100721.
[http://dx.doi.org/10.1002/cmdc.202100721] [PMID: 35157366]
[20]
Woods, C.J.; Malaisree, M.; Hannongbua, S.; Mulholland, A.J. A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies. J. Chem. Phys., 2011, 134(5), 054114.
[http://dx.doi.org/10.1063/1.3519057] [PMID: 21303099]
[21]
Tyka, M.D.; Sessions, R.B.; Clarke, A.R. Absolute free-energy calculations of liquids using a harmonic reference state. J. Phys. Chem. B, 2007, 111(32), 9571-9580.
[http://dx.doi.org/10.1021/jp072357w] [PMID: 17655215]
[22]
Monsef, R.; Ghiyasiyan-Arani, M.; Salavati-Niasari, M. Design of magenetically recyclable ternary Fe2O3/EuVO4/g-C3N4 nanocomposites for photocatalytic and electrochemical hydrogen storage. ACS Appl. Energy Mater., 2021, 4(1), 680-695.
[http://dx.doi.org/10.1021/acsaem.0c02557]
[23]
Zinatloo-Ajabshir, S.; Salavati-Niasari, M. Preparation of magnetically retrievable CoFe2O4@SiO2@Dy2Ce2O7 nanocomposites as novel photocatalyst for highly efficient degradation of organic contaminants. Compos., Part B Eng., 2019, 174, 106930-106966.
[http://dx.doi.org/10.1016/j.compositesb.2019.106930]
[24]
Zinatloo-Ajabshir, S.; Mortazavi-Derazkola, S.; Salavati-Niasari, M. Nd2O3-SiO2 nanocomposites: A simple sonochemical preparation, characterization and photocatalytic activity. Ultrason. Sonochem., 2018, 42, 171-182.
[http://dx.doi.org/10.1016/j.ultsonch.2017.11.026] [PMID: 29429658]
[25]
Davar, F.; Salavati-Niasari, M.; Fereshteh, Z. Synthesis and characterization of SnO2 nanoparticles by thermal decomposition of new inorganic precursor. J. Alloys Compd., 2010, 496(1-2), 638-643.
[http://dx.doi.org/10.1016/j.jallcom.2010.02.152]
[26]
Hassanpour, M.; Safardoust-Hojaghan, H.; Salavati-Niasari, M. Degradation of methylene blue and Rhodamine B as water pollutants via green synthesized Co3O4/ZnO nanocomposite. J. Mol. Liq., 2017, 229, 293-299.
[http://dx.doi.org/10.1016/j.molliq.2016.12.090]
[27]
Ghiyasiyan-Arani, M.; Salavati-Niasari, M.; Naseh, S. Enhanced photodegradation of dye in waste water using iron vanadate nanocomposite; ultrasound-assisted preparation and characterization. Ultrason. Sonochem., 2017, 39, 494-503.
[http://dx.doi.org/10.1016/j.ultsonch.2017.05.025] [PMID: 28732973]
[28]
Panahi-Kalamuei, M.; Alizadeh, S.; Mousavi-Kamazani, M.; Salavati-Niasari, M. Synthesis and characterization of CeO2 nanoparticles via hydrothermal route. J. Ind. Eng. Chem., 2015, 21, 1301-1305.
[http://dx.doi.org/10.1016/j.jiec.2014.05.046]
[29]
Gholami, T.; Salavati-Niasari, M.; Varshoy, S. Electrochemical hydrogen storage capacity and optical properties of NiAl2O4/NiO nanocomposite synthesized by green method. Int. J. Hydrogen Energy, 2017, 42(8), 5235-5245.
[http://dx.doi.org/10.1016/j.ijhydene.2016.10.132]
[30]
Monsef, R.; Ghiyasiyan-Arani, M.; Salavati-Niasari, M. Application of ultrasound-aided method for the synthesis of NdVO4 nano-photocatalyst and investigation of eliminate dye in contaminant water. Ultrason. Sonochem., 2018, 42, 201-211.
[http://dx.doi.org/10.1016/j.ultsonch.2017.11.025] [PMID: 29429662]
[31]
Mir, N.; Salavati-Niasari, M. Preparation of TiO2 nanoparticles by using tripodal tetraamine ligands as complexing agent via two-step sol–gel method and their application in dye-sensitized solar cells. Mater. Res. Bull., 2013, 48(4), 1660-1667.
[http://dx.doi.org/10.1016/j.materresbull.2013.01.006]
[32]
Dofe, V.S.; Sarkate, A.P.; Shaikh, Z.M.; Jadhav, C.K.; Nipte, A.S.; Gill, C.H. Ultrasound-assisted synthesis of novel pyrazole and pyrimidine derivatives as antimicrobial agents. J. Heterocycl. Chem., 2018, 55(3), 756-763.
[http://dx.doi.org/10.1002/jhet.3105]
[33]
Chate, A.V.; Kamdi, S.P.; Bhagat, A.N.; Jadhav, C.K.; Nipte, A.S.; Sarkate, A.P.; Tiwari, S.V.; Gill, C.H. Design, synthesis and SAR study of novel spiro [Pyrimido[5,4-b]Quinoline-10,50 -Pyrrolo[2,3-d]pyrimidine] derivatives as promising anticancer agents. J. Heterocycl. Chem., 2018, 55(10), 764-769.
[http://dx.doi.org/10.1002/jhet.3286]
[34]
Dofe, V.S.; Sarkate, A.P.; Shaikh, Z.M.; Gill, C.H. Ultrasound mediated synthesis of novel 1,2,3-Triazole-Based pyrazole and pyrimidine derivatives as antimicrobial agents. J. Heterocycl. Chem., 2017, 55(6), 3195-3201.
[http://dx.doi.org/10.1002/jhet.2935]
[35]
Abreu, R.M.V.; Froufe, H.J.C.; Daniel, P.O.M.; Queiroz, M.J.R.P.; Ferreira, I.C.F.R. ChemT, an open-source software for building template-based chemical libraries. SAR QSAR Environ. Res., 2011, 22(5-6), 603-610.
[http://dx.doi.org/10.1080/1062936X.2011.604097] [PMID: 21846264]
[36]
Karnik, K.S.; Sarkate, A.P.; Tiwari, S.V.; Azad, R.; Wakte, P.S. Free energy perturbation guided Synthesis with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC). Bioorg. Chem., 2021, 115, 105226-105238.
[http://dx.doi.org/10.1016/j.bioorg.2021.105226] [PMID: 34364055]
[37]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[38]
Forli, S.; Huey, R.; Pique, M.E.; Sanner, M.F.; Goodsell, D.S.; Olson, A.J. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat. Protoc., 2016, 11(5), 905-919.
[http://dx.doi.org/10.1038/nprot.2016.051] [PMID: 27077332]
[39]
Seeliger, D.; de Groot, B.L. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J. Comput. Aided Mol. Des., 2010, 24(5), 417-422.
[http://dx.doi.org/10.1007/s10822-010-9352-6] [PMID: 20401516]
[40]
Woods, C.J.; Malaisree, M.; Michel, J.; Long, B.; McIntosh-Smith, S.; Mulholland, A.J. Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water. Faraday Discuss., 2014, 169, 477-499.
[http://dx.doi.org/10.1039/C3FD00125C] [PMID: 25340314]
[41]
El-Sayed, M.A.; El-Husseiny, W.M.; Abdel-Aziz, N.I.; El-Azab, A.S.; Abuelizz, H.A.; Abdel-Aziz, A.A. Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 199-209.
[http://dx.doi.org/10.1080/14756366.2017.1407926] [PMID: 29251017]
[42]
Angelis, I.D.; Turco, L. Caco-2 cells as a model for intestinal absorption. Curr. Protoc. Toxicol., 2011, Chapter 20(1), 6.
[http://dx.doi.org/10.1002/0471140856.tx2006s47] [PMID: 21400683]
[43]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 64, 4-17.
[http://dx.doi.org/10.1016/j.addr.2012.09.019] [PMID: 11259830]
[44]
Lokwani, D.; Azad, R.; Sarkate, A.; Reddanna, P.; Shinde, D. Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors. Bioorg. Med. Chem., 2015, 23(15), 4533-4543.
[http://dx.doi.org/10.1016/j.bmc.2015.06.008] [PMID: 26122769]
[45]
Bhosle, M.R.; Khillare, L.D.; Mali, J.R.; Sarkate, A.P.; Lokwani, D.K.; Tiwari, S.V. DIPEAc promoted one-pot synthesis of dihydropyrido[2,3-d:6,5-d′]dipyrimidinetetraone and pyrimido[4,5-d]pyrimidine derivatives as potent tyrosinase inhibitors and anticancer agents: In vitro screening, molecular docking and ADMET predictions. New J. Chem., 2018, 42(23), 18621-18632.
[http://dx.doi.org/10.1039/C8NJ04622K]
[46]
Tiwari, S.V.; Seijas, J.A.; Vazquez-Tato, M.P.; Sarkate, A.P.; Karnik, K.S.; Nikalje, A.P.G. Ionic liquid-promoted synthesis of novel chromone-pyrimidine coupled derivatives, antimicrobial analysis, enzyme assay, docking study and toxicity study. Molecules, 2018, 23(2), 1-23.
[http://dx.doi.org/10.3390/molecules23020440] [PMID: 29462951]
[47]
Woods, C.J.; Malaisree, M.; Pattarapongdilok, N.; Sompornpisut, P.; Hannongbua, S.; Mulholland, A.J. Long time scale GPU dynamics reveal the mechanism of drug resistance of the dual mutant I223R/H275Y neuraminidase from H1N1-2009 influenza virus. Biochemistry, 2012, 51(21), 4364-4375.
[http://dx.doi.org/10.1021/bi300561n] [PMID: 22574858]
[48]
Kurdekar, V.; Giridharan, S.; Subbarao, J.; Nijaguna, M.B.; Periasamy, J.; Boggaram, S.; Bharatham, K.; Potluri, V.; Shivange, A.V.; Sadasivam, G.; Padigaru, M.; Venkitaraman, A.R. Structural features underlying the activity of benzimidazole derivatives that target phosphopeptide recognition by the tandem BRCT domain of the BRCA1 protein. bioRxiv,
[http://dx.doi.org/10.1101/555623]
[49]
Liu, J.; Liu, L.; Tian, Z.; Li, Y.; Shi, C.; Shi, J.; Wei, S.; Zhao, Y.; Zhang, C.; Bai, B.; Chen, Z.; Zhang, H. In silico discovery of a small molecule suppressing lung carcinoma A549 cells proliferation and inducing autophagy via mTOR pathway inhibition. Mol. Pharm., 2018, 15(11), 5427-5436.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00996] [PMID: 30346178]
[50]
Patel, H.; Pawara, R.; Ansari, A.; Surana, S. Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance. Eur. J. Med. Chem., 2017, 142, 32-47.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.027] [PMID: 28526474]

Rights & Permissions Print Cite
Article Metrics
18
2
© 2024 Bentham Science Publishers | Privacy Policy