Abstract
In the paper we review the application of two techniques (molecular mechanics and quantum mechanics) to study the influence of geometry optimization of the steroid sulfatase inhibitors on the values of descriptors coded their chemical structure and their free binding energy with the STS protein. We selected 22 STS-inhibitors and compared their structures optimized with MM+, PM7 and DFT B3LYP/6–31++G* approaches considering separately the bond lengths, angles, dihedral angles and total energies. We proved that different minimum energy conformers could be generated depending on the choice of the optimization method. However, the results indicated that selection of the geometry optimization method did not affect the optimal STS inhibitor coordinates, and hence the values of molecular descriptors which describe the 3D structure of the molecule. To study the interaction pattern of the STS inhibitors (optimized using different methods) with the target receptor we applied two strategies: AutoDock and PathDock. The docking studies point out that selection of software to docking simulation is one of the crucial factors determining the binding mode of STS inhibitors with their molecular target. Other factor is related to the ligand orientation in the binding pocket. Finally, obtained results indicate that MM+ and PM7 methods (faster and less expensive) could be successfully employed to geometry optimization of the STS inhibitors before their docking procedure as well as for molecular descriptors calculations.
Highlights
Over the past decades, numerous reports have suggested that the biologically active hormone precursors may affect on cellular proliferation in various cancers [1]
The geometry of the compounds was optimized in the vacuum by two different methods: (i) the molecular mechanics (MM) using the MM+ force field and the Polak-Ribiere conjugate gradient algorithm terminating at the gradient of 0.05 kcal mol−1 Å−1
We have applied: (i) the molecular mechanics using the MM+ force field and the Polak-Ribiere conjugate gradient algorithm terminating at the gradient of 0.05 kcal mol−1 Å−1; (ii) the quantum-mechanics using semi-empirical PM7 level; and Density Functional Theory (DFT) B3LYP with the 6– 31++G* basis set
Summary
Numerous reports have suggested that the biologically active hormone precursors may affect on cellular proliferation in various cancers [1] These compounds (including androgens and estrogens) play an important role in the development of many diseases, such as hormonedependent breast cancer (HDBC) [1]. One approach for treatment of the HDBC involves inhibitors of enzymes responsible for the biosynthesis of estrogens in peripheral tissues, e.g., steroid sulfatase (STS) [1]. The presence of experimentally determined structure of target molecule would allow following the second type of methodology This includes the molecular docking (MD) [20], QM-Polarized Ligand Dicking (QPLD) [21] or/and the three-dimensional quantitative-structure activity relationships (3D QSAR) [22, 23]. Due to the fact that the initial step both in molecular docking and 3D QSAR modelling involves the geometry optimization of the STS inhibitors, the main goal of our study (the first step according to application of SBDD) is to: (i) compare the geometries of the STS inhibitor structures after the optimization with methods differ in theory level; (ii) evaluate the impact of the geometry optimization on the values of descriptors coded chemical structure of STS inhibitors, and (iii) verify if the method applied to optimize the structures influence their free binding energy with the STS protein
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