Dataset Information

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation.

ABSTRACT: Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.In the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models' validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.The made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.The QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.

SUBMITTER: Abbasi M

PROVIDER: S-EPMC5493083 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation.

Abbasi Maryam M Sadeghi-Aliabadi Hojjat H Amanlou Massoud M

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences 20170630 1

<h4>Background</h4>Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.<h4>Methods</h4>In the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The ...[more]

PMID: 28666484

Similar Datasets

Project description:The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

Project description:Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (q2 = 0.751, ONC = 4, r2 = 0.911) model revealed reasonable statistical results. Overall results of molecular dynamics simulation, MM-PBSA binding free energy calculation and RF-CoMFA model revealed important active site residues of IRAK4 and necessary structural properties of ligand to design more potent IRAK4 inhibitors. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC50) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.

Dataset Information

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation.

Publications

Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets