Bimodal Complexations of Steroids with Cyclodextrins by a Flexible Docking Algorithm (original) (raw)
Related papers
Molecular modeling methodology of β-cyclodextrin inclusion complexes
Journal of Molecular Structure: THEOCHEM, 1996
A docking approach for molecular mechanics optimization of P-cyclodextrin complexes is described. Because of the specific geometry of the cyclodextrins and the class of guests (relatives of tert-butyl benzene), the guest molecule is moved along a vector going through the middle of the cavity. This vector is perpendicular to the mean plane of the a&al oxygen atoms that link the glucose units. At each step along this vector, the geometry of the bimolecular assembly was optimized to give a minimum in the molecular mechanics steric energy. As expected, the energy decreases as the guest molecule enters the cyclodextrin cavity, and again increases as the guest exits from the other side of the cavity. Rotation of the guest within the cavity prior to energy minimization did not result in lower energies; the minimization process found the best rotational orientation of the guest. On the other hand, it was necessary to drive the guest along the vector; the energy minimization process did not pull the guest into an optimal depth of penetration into the cavity. The binding energies calculated at two different dielectric constants were almost identical, indicating that the complex formation is stabilized by dispersive or Van der Waals forces and not electrostatic (dipole-dipole or hydrogen bonding) forces.
Ab Initio Evaluation of Complexation Energies for Cyclodextrin-Drug Inclusion Complexes
ACS Omega
We investigated the reliability of ab initio methods to predict the binding energies of molecular encapsulation complexes. Vast possibilities for the docking conformations were screened down to a couple of geometries using a semiempirical docking simulation. For the candidates, we applied density functional theory (DFT) with several exchange−correlation (XC) functionals to evaluate the binding energy. We carefully selected and compared the functionals to elucidate the role of the characteristic factors in achieving the XC effects. It is clarified that the improper combination in XC with D3 dispersion force correction leads to overbinding. For achieving a proper combination, the exchange interaction over the longer range to avoid the overbinding was found to be important.
Interaction Energy Analysis for Drug-Cyclodextrin Inclusion Complexes in Aqueous Solutions
Journal of Applied Solution Chemistry and Modeling, 2012
It is vital to elucidate the role of asymmetric intermolecular interactions resulting from the stereospecific structures of molecules in order to understand the mechanisms of chemical and biochemical reactions such as enzymesubstrate reactions, antigen-antibody reactions, etc. In order to reveal the mechanism of the inclusion phenomenon for β-cyclodextrin (CD)-ampicillin complexes and β-CD-ibuprofen complexes, binding free energies were determined using molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis. To clarify the details of the interaction energies of these complexes, pair interaction energy decomposition analysis (PIEDA) was carried out. The direction of inclusion of drugs into β-CD cavities was clarified on the basis of results obtained using the above-mentioned methods.
Journal of Molecular Graphics and Modelling, 2000
An extension of the computer program CICADA has been developed that allows us to use the single-coordinatedriving (SCD) method for flexible molecular docking. The docking procedure is composed of three independent space rotations, three independent translations, and the torsions selected by the user. One of the coordinates is driven; the other coordinates are relaxed. This procedure follows lowenergy wells on the potential energy surface of the entire system. The program allows us to dock more than one ligand molecule to the receptor. We ran two test examples, docking N,N-dimethylformamide into alpha-cyclodextrin and Rphenoxypropionic acid into beta-cyclodextrin. The test examples showed that the SCD approach is able to overcome high-energy barriers and to cover the entire box within which the search is performed. The limitations of molecular dynamics docking in comparison with our approach also are discussed. The philosophy of the newly developed approach is not only to find the best dock for the receptor-ligand(s) system, but also to describe all the important binding modes and provide a good starting point for studying the dynamics within the cavity during the docking process.
Molecular interactions of α-cyclodextrin inclusion complexes using a genetic algorithm
Journal of Molecular Structure: THEOCHEM, 2001
Molecular interactions of inclusion complexes of mono-or 1,4-disubstituted benzenes and a-cyclodextrin have been studied in this paper. Two types of energy terms were considered in the total interaction energies, non-bonded term and desolvation term, and minimized by a genetic algorithm (GA). Using the consistent force ®eld (CFF91), the non-bonded energies between all pairs of atoms in different molecules were determined by a Coulomb potential term for electrostatic interactions and a Lennard-Jones potential for van der Waals interactions. The desolvation energy term was modeled by a simple constant term corresponding to a penalty when polar atoms are placed in the hydrophobic cavity. The total interaction energies for 15 inclusion complexes with experimental association constants (ln K) were optimized by the GA method. Linear regression analysis of the observed association constants against the total energies was performed. It was found that the interaction energies of these complexes obtained by the simple interaction energy model could be correlated with their experimental association constants, and also the desolvation term should be included.
Arkivoc, 2002
The complex formation of five steroidal heterocyclic compounds (1-5) with β-cyclodextrin and hydroxypropyl-β-cyclodextrin was investigated in aqueous solution and in solid state in order to find the strenght of interaction. The complex formation of these steroidic compounds with CDs in aqueous solution was studied by solubility analysis and ultraviolet absorption methods. For the study of solid state interaction, solid complexes were prepared by the solvent evaporation method and complexes obtained were analysed by thermal analysis. Also, synthesis, NMR and IR data of the new steroidic compounds 1,2, and 3are presented.
Estimation of cyclodextrin affinity to steroids
Journal of Pharmacy and Pharmacology, 2002
A nonlinear spectrometric method for determination of the stability constant (K S) for cyclodextrin complex with steroid was developed. The method is based on calculation of the parameters of competitive cyclodextrin complexation by simultaneous tting of two types of curves. Those of the rst type are the dependencies of absorbance of methyl orange solution on the cyclodextrin concentration, the second type being the absorption curves of displacement of the dye, by steroid, from the cyclodextrin complex. With the method proposed, K S values were calculated with standard deviation less than 10 %. This method is validated by determination of K S values using the phase-solubility technique. For neutral steroid molecules, the effect of pH on K S was found to be insigni cant. K S values for the cyclodextrin-dye complex were determined for randomly methylated b-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin, carboxymethyl-b-cyclodextrin and sulfobutylether-b-cyclodextrin. More hydrophobic steroids were characterised by higher K S values. Anionic b-cyclodextrins showed high af nity for the steroids studied. Simple equipment and suf cient computing allowed recommendation of the method for express estimation of cyclodextrin's af nity for hydrophobic substrates.
An in-depth theoretical analysis of two monosubstituted cyclodextrins (CDs) has been performed in order to find the appropriate level of theory capable of the correct qualitative description of their experimentally evidenced self-inclusion phenomenon. The correct increased stability of conformations with substituents included into the cavity ('IN' conformations) compared with those in which sub-stituents point outside the cavity ('OUT' conformations) is qualitatively predicted by molecular mechanics , the dispersion-corrected self-consistent-charge density-functional tight-binding (SCC-DFTB-D), dispersion-corrected density-functional theory (DFT-D), single-point second-order MøllerePlesset (MP2), and domain based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) computations. The latter four approaches provide also quantitative insights into the relative stability of the 'IN' and 'OUT' conformations. The method of choice for the fast evaluation of the stability order of the CD conforma-tions is the SCC-DFTB-D that yields relative energies with nearly DFT-D and MP2 accuracy.
Chemical Physics Letters, 2002
Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants (K s) and some theoretical parameters describing complexation (docking energy, hostguest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum conformational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model (r ¼ 0:897) related log K s with complex docking energy and lipophilic molecular fields of cyclodextrin and drug.
Journal of Molecular Liquids, 2016
In the present investigation, a combination of docking and quantitative structure-property relationship (QSPR) approaches was applied to elucidate the host-guest interactions in β-cyclodextrin complexation with diverse set of organic compounds. Molecular docking was performed to find correct conformations of organic molecules in the cavity of β-cyclodextrin. The conformation with the lowest binding free energy was chosen to calculate molecular descriptors. Some additional descriptors relevant to characterizing the structural properties of inclusion complexes were also calculated and used in QSPR model building. Genetic function approximation technique was applied to choose the best subset of descriptors. The selected descriptors explain that the hydrophobicity, surface area and shape of guest molecules play important roles in the β-cyclodextrin complexation. The final QSPR model, based on multiple linear regression (MLR) method, was characterized by satisfactory statistical performance; calibration (R 2 c) and prediction (R 2 p) correlation coefficient of 0.83 ± 0.02 and 0.78 ± 0.07 respectively.