3D-QSAR, DOCKING STUDY, PHARMACOPHORE MODELING AND ADMET PREDICTION OF 2-AMINO-PYRAZOLOPYRIDINE DERIVATIVES AS POLO-LIKE KINASE 1 INHIBITORS
Keywords:
Polo-like kinase 1 inhibitors, 3D-QSAR, kNN-MFA model, Docking study, Pharmacophore modeling, ADMET propertiesAbstract
Objective: The polo-like kinase 1 (plk1) plays important roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation and cytokinesis. Thus, plk1 is considered as a good target for chemotherapeutic intervention. The main objectives of this research were to in silico screen the 2-amino-pyrazolopyridine derivatives as plk1 inhibitors and develop pharmacophore for enhanced activity.
Methods: The three-dimensional quantitative structure–activity relationship (3D-QSAR), docking and pharmacophore identification studies on 2-amino-pyrazolopyridine derivatives as plk1 inhibitors have been carried out using V Life MDS 4.3 software. The stepwise 3D-QSAR kNN-MFA method was applied to derive QSAR model. Also, ADMET prediction was performed using FAF Drugs 2 which runs on Linux OS.
Results: The information rendered by 3D-QSAR models may lead to a better understanding and designing of novel plk1 inhibitor molecules. The molecular docking analysis was carried out to better understand the interactions between plk1 enzyme and inhibitors in this series. Hydrophobic and hydrogen bond interactions lead to identification of active binding sites. The results of pharmacophore studies showed that hydrogen bond accepters, aromatic and aliphatic centers are the important features for polo-like kinase 1 inhibitor activity. ADMET prediction of these compounds showed good drug like properties.
Conclusion: The combination of the 3D-QSAR, docking, pharmacophore modeling and ADMET prediction is an important tool in understanding the structural requirements for design of novel, potent and selective plk1 inhibitors and can be employed to design new  drug discovery and can be used for derivatives of 2-amino-pyrazolopyridines with specific plk1 inhibitory activity.
Downloads
References
Jain SV, Bhadoriya KS, Bari SB, Sahu NK, Ghate M. Discovery of Potent Anticonvulsant Ligands as Dual NMDA and AMPA Receptors Antagonists by Molecular Modeling Studies. Med Chem Res 2012;21 (11):3465-84.
Hadjipavlou-Litina D. Review, Reevaluation, and New Results in Quantitative Structure-Activity Studies of Anticonvulsants. Med Res Rev 1998;18 (2):91-119.
Bhadoriya KS, Jain SV, Bari SB, Chavhan ML, Vispute KR. 3D-QSAR Study of Indol-2-yl Ethanones Derivatives as Novel Indoleamine 2,3-Dioxygenase (IDO) Inhibitors. J Chem 2012;9 (4):1753-59.
Barr FA, Sillje HHW, Nigg EA. Polo-Like Kinases and the Orchestration of Cell Division. J Nat Rev Mol Cell Biol 2004;5 (6):429-41. (b) Glover DM, Hagan IM, Tavares AAM. Polo-Like Kinases:A Team that Plays Throughout Mitosis. Genes Dev 1998;12 (24):3777-87.
De Carcer G, Escobar B, Higuero AM, Garcia L, Anson A, Perez G, et al. Plk5, A Polo Box Domain-Only Protein with Specific Roles in Neuron Differentiation and Glioblastoma Suppression. Mol Cell Biol 2011;31 (6):1225-39.
Degenhardt Y, Lampkin T. Targeting Polo-like Kinase in Cancer Therapy. Clin Cancer Res 2010;16 (2):384-89.
Strebhardt K, Ullrich A. Targeting Polo-Like Kinase 1 for Cancer Therapy. Nat Rev Cancer 2006;6 (4):321-30.
Strebhardt K. Multifaceted Polo-Like Kinases:Drug Targets and Antitargets for Cancer Therapy. Nat Rev Drug Discov 2010;9 (8):643-60.
Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, et al. BI 2536, a Potent and Selective Inhibitor of Polo-Like Kinase 1, Inhibits Tumor Growth in Vivo. Curr Biol 2007;17 (4):316-22.
Elez R, Piiper A, Kronenberger B, Kock M, Brendel M, Hermann E, et al. Tumor Regression by Combination Antisense Therapy Against Plk1 And Bcl-2. Oncogene 2003;22 (1):69–80.
Spankuch-Schmitt B, Wolf G, Solbach C, Loibl S, Knecht R, Stegmuller M, et al. Downregulation of Human Polo-Like Kinase Activity by Antisense Oligonucleotides Induces Growth Inhibition in Cancer Cells. Oncogene 2002;21 (20):3162-71.
Eckerdt F, Yuan J, Strebhardt K. Polo-Like Kinases and Oncogenesis. J Oncogene 2005;24 (2):267-76.
Takai N, Hamanaka R, Yoshimatsu, Miyakawa I. Polo-Like Kinases (Plks) and Cancer. Oncogene 2005;24 (2):287-91.
Strebhardt K, Ullrich A. Targeting Polo-Like Kinase 1 for Cancer Therapy. Nat Rev Cancer 2006;6 (4):321-30.
Sangshetti JN, Shinde DB. Synthesis of Some Novel 3-(1-(1-Substitutedpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-substituted phenyl-1,2,4-oxadiazoles as Antifungal Agents. Eur J Med Chem 2011;46 (4):1040-44. (b) Sangshetti JN, Nagawade RR, Shinde DB. Synthesis of Novel 3-(1-(1-Substitutedpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-5(4H)-one as Antifungal Agents. Bioorg Med Chem Lett 2009;19 (13):3564-67. (c) Sangshetti JN, Shinde DB. One Pot Synthesis and SAR of Some Novel 3-Substituted-5,6-diphenyl-1,2,4-triazines as Antifungal Agents. Bioorg Med Chem Lett 2010;20 (2):742-45. (d) Sangshetti JN, Dharmadhikari PP, Chouthe RS, Fatema B, Lad V, Karande V, Darandale SN, Shinde DB. Microwave Assisted Nano (ZnO–TiO2) Catalyzed Synthesis of Some New 4,5,6,7-Tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as Antimicrobial Agents. J Bioorg Med Chem Lett 2013;23 (7):2250-53. (e) Sangshetti JN, Lokwani DK, Sarkate AP, Shinde DB. Synthesis, Antifungal Activity, and Docking Study of Some New 1,2,4-Triazole Analogs. J Chem Biol Drug Des 2011;78 (5):800-09.
Sangshetti JN, Chabukswar AR, Shinde DB. Microwave Assisted One Pot Synthesis of Some Novel 2,5-Disubstituted-1,3,4-oxadiazoles as Antifungal Agents. Bioorg Med Chem Lett 2011;21 (1):444-48. (b) Sangshetti JN, Shaikh RI, Khan FAK, Patil RH, Marathe SD, Gade WN, Shinde DB. Synthesis, Antileishmanial Activity and Docking Study of N′-Substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-C]pyridin-5(4H)-yl)acetohydrazides. Bioorg Med Chem Lett 2014;24 (6):1605–10. (c) Sangshetti JN, Khan FAK, Chouthe RS, Damale MG, Shinde DB. Synthesis, Docking and ADMET Prediction of Novel 5-((5-Substituted-1-H-1,2,4-triazol-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine as Antifungal Agents. Chinese Chem Lett 2014;25 (7):1033-38.
VLife Molecular Design Suite 4.3, VLife Sciences Technologies Pvt. Ltd;www.Vlifesciences.com.
Fucini RV, Hanan EJ, Romanowski MJ, Elling RA, Lew W, Barr KJ, et al. Design and Synthesis of 2-Amino-pyrazolopyridines as Polo-Like Kinase 1 Inhibitors. Bioorg Med Chem Lett 2008;18 (20):5648-52.
Halgren TA. Molecular Geometries and Vibrational Frequencies for MMFF94. J Comput Chem 1996;17 (5-6):553–86.
Cramer RD, Patterson DE, Bunce JD. Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins. Am Chem Soc 1988;110 (18):5959–67.
Sharaf MA, Illman DL, Kowalski BR. Chemometrics. Wiley (NY);1986.
Elling RA, Fucini RV, Romanowski MJ. Structures of the Wild-Type and Activated Catalytic Domains of Brachydanio Rerio Polo-Like Kinase 1 (Plk1):Changes in the Active-Site Conformation and Interactions with Ligands. Acta Crystallogr Sect D 2008;64 (9):909-18.
Lagorce D, Sperandio H, Miteva MA, Villoutreix BO. FAF-Drugs2:Free ADME/Tox Filtering Tool to Assist Drug Discovery and Chemical Biology Projects. BMC Bioinformatics 2008;9:396.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv Drug Deliv Rev 2001;46 (1-3):3-26.
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J Med Chem 2002;45 (12):2615-23.
Ertl P, Rohde B, Selzer P. Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties. J Med Chem 2000;43 (20):3714-17.