Peter Wolschann - Academia.edu (original) (raw)

Papers by Peter Wolschann

Research paper thumbnail of Thermodynamic Investigations on the Inclusion Complexation of Piroxicam with Cyclodextrin Derivatives

Scientia Pharmaceutica, 2005

Thermodynamic studies of piroxicam in aqueous solution complexed with β-cyclodextrin (β-CD), γ-cy... more Thermodynamic studies of piroxicam in aqueous solution complexed with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and two β-cyclodextrin derivatives, hydroxypropyl-β-cyclodextrin (HP-P-CD) and methyl-β-cyclodextrin (Me-β-CD) were performed at different temperatures and pH values using the phase solubility method. The phase solubility diagrams of β-CD, γ-CD and HP-β-CD is of AL-type behavior, indicating the formation of 1:l complexes. The related stability constants range from β-CD > γ-CD > Me-β-CD > HP-β-CD, respectively. An Ap-type solubility diagram is observed for Me-β-CD, indicating the formation of 1:2 complexes at higher CD concentrations. From the temperature dependence of the equilibrium constants the reaction enthalpies and entropies have been determined. The contributions of the reaction entropies are small and no enthalpy-entropy-compensation is observed, except for γ-CD, where a very small negative reaction entropy could be estimated. Moreover, the influence of...

Research paper thumbnail of Theoretical study on the intramolecular hydrogen bond in chloro-substituted N,N-dimethylaminomethylphenols. I. Structural effects

Journal of Molecular Structure, Mar 1, 2004

Ab initio and density functional calculations are applied to study the influence of an increasing... more Ab initio and density functional calculations are applied to study the influence of an increasing number of chlorine substituents on the properties of the intramolecular hydrogen bond in substituted Mannich bases. It is shown, that not only the acidity of the proton donor, which depends on the number of chlorine atoms at the aromatic ring, but also steric interactions modify the geometry of the hydrogen bond. Specific interactions of O-Cl• • •H-O hydrogen-bonding in some derivatives are estimated by calculations on related chlorophenols.

Research paper thumbnail of Threshold-Based Structure−Activity Relationships of Pyrazines with Bell-Pepper Flavor

Journal of Agricultural and Food Chemistry, Aug 4, 2000

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (Co... more Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Research paper thumbnail of Free Energy Prediction of the Complexation between β -Cyclodextrin and Guest Molecules: External Predictivity of MR and PLS Models

Scientia Pharmaceutica, Mar 2, 2000

Dipeptidamides as Sweeteners 165 Several L-Aspartyl-D-alanin-2-methylcyc1oalkylamides (9a-h) were... more Dipeptidamides as Sweeteners 165 Several L-Aspartyl-D-alanin-2-methylcyc1oalkylamides (9a-h) were synthesized and tested for their sweet quality.

Research paper thumbnail of Density Functional Theory Calculations on Methylated β-Cyclodextrins

Scientia Pharmaceutica, 2010

Research paper thumbnail of Quantitative Structure-Property Study on Pyrazines with Bell Pepper Flavor

Scientia Pharmaceutica, Mar 5, 2000

A quantitative structure-property (QSPR) study on pyrazines with bell pepper aroma is performed b... more A quantitative structure-property (QSPR) study on pyrazines with bell pepper aroma is performed by means of different statistical methods, which correlate appropriate molecular descriptors with the biological activity. The different methods lead to consistent results, indicating which of the molecular properties of the compounds under consideration are significant for bell pepper flavor. These results are compared with other models.

Research paper thumbnail of Theoretical studies on RNA recognition by Musashi 1 RNA-binding protein

Scientific Reports

The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) an... more The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI–RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1–RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MS...

Research paper thumbnail of Effect of Water Microsolvation on the Excited-State Proton Transfer of 3-Hydroxyflavone Enclosed in γ-Cyclodextrin

Molecules, 2021

The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone... more The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone (3HF) and its inclusion complex with γ-cyclodextrin (γ-CD) was studied using computational approaches. From molecular dynamics simulations, two possible inclusion complexes formed by the chromone ring (C-ring, Form I) and the phenyl ring (P-ring, Form II) of 3HF insertion to γ-CD were observed. Form II is likely more stable because of lower fluctuation of 3HF inside the hydrophobic cavity and lower water accessibility to the encapsulated 3HF. Next, the conformation analysis of these models in the ground (S0) and the first excited (S1) states was carried out by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations, respectively, to reveal the photophysical properties of 3HF influenced by the γ-CD. The results show that the intermolecular hydrogen bonding (interHB) between 3HF and γ-CD, and intramolecular hydrogen bonding (intraHB) within 3HF are strengthened in the...

Research paper thumbnail of Accessible Charges in Structure-Activity Relationships. A Study on HEPT-based HIV-1 RT Inhibitors

Scientia Pharmaceutica, 2000

The solvent accessibility of charges is introduced in QSAR studies. Atomic charges which do have ... more The solvent accessibility of charges is introduced in QSAR studies. Atomic charges which do have contribution to the biological activity of a compound are more or less exposed to the environment (solvent), i.e. they have different possibilities to interact with biological macromolecules. Although one can imagine different ways in considering solvent accessibility, in this work it is taken into account by multiplying the net charge of an atom with its solvent accessible surface. To study the effect of accessibility of a charge on a biological activity, a large set (of 101) HEPT-based HIV- 1 reverse transcriptase (RT) inhibitors is analyzed, a molecu1a.r system, where the importance of electronic contribution is known. The results, based on multiple linear regression (MLR) and partial least squares (PLS) analysis, show that accessible charges correlate better with the RT inhibitory activity than net charges, leading to models with higher predictive ability.

Research paper thumbnail of Interactions of HLA-DR and Topoisomerase I Epitope Modulated Genetic Risk for Systemic Sclerosis

Scientific Reports, 2019

The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific a... more The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific alleles of human leukocyte antigen (HLA)-DR has been observed among various ethnics. The anti-Topoisomerase 1 antibody is a common autoantibody in SSc with diffuse cutaneous scleroderma, which is one of the clinical subtypes of SSc. On the other hand, an immunodominant peptide of topoisomerase 1 (Top1) self-protein (residues 349–368) was reported to have strong association with ATASSc. In this study, molecular dynamics simulation was performed on the complexes of Top1 peptide with various HLA-DR subtypes divided into ATASSc-associated alleles (HLA-DRB1*08:02, HLA-DRB1*11:01 and HLA-DRB1*11:04), suspected allele (HLA-DRB5*01:02), and non-associated allele (HLA-DRB1*01:01). The unique interaction for each system was compared to the others in terms of dynamical behaviors, binding free energies and solvation effects. Our results showed that three HLA-DR/Top1 complexes of ATASSc association mo...

Research paper thumbnail of Computational screening of chalcones acting against topoisomerase IIα and their cytotoxicity towards cancer cell lines

Journal of Enzyme Inhibition and Medicinal Chemistry, 2018

Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomera... more Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIa by computational techniques, and subsequently tested for their in vitro cytotoxicity. From the experimental IC 50 values, chalcone 3d showed a high cytotoxicity with IC 50 values of 10.8, 3.2 and 21.1 mM against the HT-1376, HeLa and MCF-7 cancer-derived cell lines, respectively, and also exhibited an inhibitory activity against hTopoIIa-ATPase that was better than the known inhibitor, salvicine. The observed ligand-protein interactions from a molecular dynamics study affirmed that 3d strongly interacts with the ATP-binding pocket residues. Altogether, the newly synthesised chalcone 3d has a high potential to serve as a lead compound for topoisomerase inhibitors.

Research paper thumbnail of Molecular recognition of naphthoquinone-containing compounds against human DNA topoisomerase IIα ATPase domain: A molecular modeling study

Journal of Molecular Liquids, 2017

Research paper thumbnail of Structural Analysis of Host–Guest Systems. Methyl-substituted Phenols in beta;-Cyclodextrin

Journal of Inclusion Phenomena

Complexation trajectories and the variation of induced circular dichroism are calculated for the ... more Complexation trajectories and the variation of induced circular dichroism are calculated for the docking of phenol and 2,4,6-trimethyl-phenol with-cyclodextrin. The results are compared to experimental chirality data to elucidate the mechanism of nonspecific molecular recognition processes in aqueous solution. Large geometrical changes along nearly isoenergetic Dynamic Monte Carlo trajectories show the conformational flexibility of such host-guest systems. This proves diffuse intermolecular interactions, van der Waals or electrostatic in nature, as the main contributions to the binding energy. The number and position of the methyl substituents of the guest reduces the complexity of the conformational space as the guest's position becomes fixed by steric constraints. The solvation free energy is calculated from the solvent accessible surface area weighted by respective atomic solvation parameters. Considering the solvation term in the dynamic simulations restricts the conformational flexibility of the macromolecular system. The relative importance of various contributions to the solvation energy is discussed and it is shown that those terms arising from the interaction of hydrophobic groups with the aqueous environment are essential for the determination of the complex structure. Considering these terms in the dynamic simulation model, the sign and strength of the calculated rotatory strength is in perfect agreement with induced circular dichroism obtained from experimentally determined averaged spectra. The results demonstrate the accuracy of the geometrical properties of host-guest systems obtained from these simulations.

Research paper thumbnail of Internally defined distances in 3D-quantitative structure-activity relationships

Journal of Computer-Aided Molecular Design

Research paper thumbnail of Predicting the Free Energies of Complexation Between Cyclodextrins and Guest Molecules: Linear versus Nonlinear Models

Pharmaceutical Research, 2000

Purpose. In the present paper, linear and nonlinear models forcomplexation of a- ß- and ?-cyclode... more Purpose. In the present paper, linear and nonlinear models forcomplexation of a- ß- and ?-cyclodextrin with guest molecules are developed,with the aim of free energy prediction and interpretation of theassociation process.

Research paper thumbnail of Influence of solvation on helix formation of poly-alanine studied by multiple annealing simulations

Journal of Molecular Structure: THEOCHEM, 1996

The influence of solvation on a-helix formation is studied for a 14-residue homoalanine and a 16-... more The influence of solvation on a-helix formation is studied for a 14-residue homoalanine and a 16-residue alanine-based polypeptide, in aqueous solution. Four variants of Dynamic Monte Carlo @MC) simulations, using a multiple annealing procedure are performed. The results obtained under in vacua conditions are compared to simulations considering either contributions to the solvation energy of non-favourable solvent interactions by hydrophobic groups, or the total solvation energy, both calculated by a continuum approximation. The highest average helix lengths are found when the total solvation energy (hydrophilic and hydrophobic contributions) is considered, although solvation counteracts the formation of compact peptide structures. The influence of solvation on helix formation is discussed.

Research paper thumbnail of A Method for Predicting the Free Energies of Complexation between β-Cyclodextrin and Guest Molecules

Journal of Inclusion Phenomena and Macrocyclic Chemistry - J INCL PHENOM MACROCYCL CHEM, 2000

In the present work, linear regression models for theprediction of the free energies of complexat... more In the present work, linear regression models for theprediction of the free energies of complexationbetween guest molecules and ß-cyclodextrin arededuced. For 70 compounds (mostly pharmaca), theexperimentally determined 1 : 1 stability constants aretransformed into the respective free energies, whichare then correlated with molecular descriptors.

Research paper thumbnail of Molecular dynamics simulations and quantum chemical calculations on β-cyclodextrin spironolactone complex

Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2007

Molecular dynamics simulations on b-cyclodextrin in vacuo, with water and complexed with spironol... more Molecular dynamics simulations on b-cyclodextrin in vacuo, with water and complexed with spironolactone (SP) were performed at a temperature of 300 K over a period of 1 ns. Two different orientations of SP in the cavity were considered. Along with conformational parameters, the formation of hydrogen bonds has been monitored during the whole simulation time. Cyclodextrins have the capability to form hydrogen bonds with the surrounding water molecules or intramolecular ones. The incorporation of ligands into the hydrophobic interior of b-cyclodextrin changes the preference of hydrogen bonds significantly and results in a contribution to the decrease of flexibility. Quantum chemical calculations on SP-b-CD inclusion complex were performed to determine the interaction energy and to prove the applicability of various methods. Although all applied methods describe reasonable geometries for the association complex, higher level methods (e.g., B3LYP/6-31G(d,p)) seem to be necessary to determine reliable interaction energies.

Research paper thumbnail of Threshold-Based Structure−Activity Relationships of Pyrazines with Bell-Pepper Flavor

Journal of Agricultural and Food Chemistry, 2000

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (Co... more Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Research paper thumbnail of Theoretical study on the intramolecular hydrogen bond in chloro-substituted N,N-dimethylaminomethylphenols. I. Structural effects

Journal of Molecular Structure, Aug 1, 2004

Ab initio and density functional calculations are applied to study the influence of an increasing... more Ab initio and density functional calculations are applied to study the influence of an increasing number of chlorine substituents on the properties of the intramolecular hydrogen bond in substituted Mannich bases. It is shown, that not only the acidity of the proton donor, which depends on the number of chlorine atoms at the aromatic ring, but also steric interactions modify the geometry of the hydrogen bond. Specific interactions of O-Cl• • •H-O hydrogen-bonding in some derivatives are estimated by calculations on related chlorophenols.

Research paper thumbnail of Thermodynamic Investigations on the Inclusion Complexation of Piroxicam with Cyclodextrin Derivatives

Scientia Pharmaceutica, 2005

Thermodynamic studies of piroxicam in aqueous solution complexed with β-cyclodextrin (β-CD), γ-cy... more Thermodynamic studies of piroxicam in aqueous solution complexed with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and two β-cyclodextrin derivatives, hydroxypropyl-β-cyclodextrin (HP-P-CD) and methyl-β-cyclodextrin (Me-β-CD) were performed at different temperatures and pH values using the phase solubility method. The phase solubility diagrams of β-CD, γ-CD and HP-β-CD is of AL-type behavior, indicating the formation of 1:l complexes. The related stability constants range from β-CD > γ-CD > Me-β-CD > HP-β-CD, respectively. An Ap-type solubility diagram is observed for Me-β-CD, indicating the formation of 1:2 complexes at higher CD concentrations. From the temperature dependence of the equilibrium constants the reaction enthalpies and entropies have been determined. The contributions of the reaction entropies are small and no enthalpy-entropy-compensation is observed, except for γ-CD, where a very small negative reaction entropy could be estimated. Moreover, the influence of...

Research paper thumbnail of Theoretical study on the intramolecular hydrogen bond in chloro-substituted N,N-dimethylaminomethylphenols. I. Structural effects

Journal of Molecular Structure, Mar 1, 2004

Ab initio and density functional calculations are applied to study the influence of an increasing... more Ab initio and density functional calculations are applied to study the influence of an increasing number of chlorine substituents on the properties of the intramolecular hydrogen bond in substituted Mannich bases. It is shown, that not only the acidity of the proton donor, which depends on the number of chlorine atoms at the aromatic ring, but also steric interactions modify the geometry of the hydrogen bond. Specific interactions of O-Cl• • •H-O hydrogen-bonding in some derivatives are estimated by calculations on related chlorophenols.

Research paper thumbnail of Threshold-Based Structure−Activity Relationships of Pyrazines with Bell-Pepper Flavor

Journal of Agricultural and Food Chemistry, Aug 4, 2000

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (Co... more Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Research paper thumbnail of Free Energy Prediction of the Complexation between β -Cyclodextrin and Guest Molecules: External Predictivity of MR and PLS Models

Scientia Pharmaceutica, Mar 2, 2000

Dipeptidamides as Sweeteners 165 Several L-Aspartyl-D-alanin-2-methylcyc1oalkylamides (9a-h) were... more Dipeptidamides as Sweeteners 165 Several L-Aspartyl-D-alanin-2-methylcyc1oalkylamides (9a-h) were synthesized and tested for their sweet quality.

Research paper thumbnail of Density Functional Theory Calculations on Methylated β-Cyclodextrins

Scientia Pharmaceutica, 2010

Research paper thumbnail of Quantitative Structure-Property Study on Pyrazines with Bell Pepper Flavor

Scientia Pharmaceutica, Mar 5, 2000

A quantitative structure-property (QSPR) study on pyrazines with bell pepper aroma is performed b... more A quantitative structure-property (QSPR) study on pyrazines with bell pepper aroma is performed by means of different statistical methods, which correlate appropriate molecular descriptors with the biological activity. The different methods lead to consistent results, indicating which of the molecular properties of the compounds under consideration are significant for bell pepper flavor. These results are compared with other models.

Research paper thumbnail of Theoretical studies on RNA recognition by Musashi 1 RNA-binding protein

Scientific Reports

The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) an... more The Musashi (MSI) family of RNA-binding proteins, comprising the two homologs Musashi-1 (MSI1) and Musashi-2 (MSI2), typically regulates translation and is involved in cell proliferation and tumorigenesis. MSI proteins contain two ribonucleoprotein-like RNA-binding domains, RBD1 and RBD2, that bind single-stranded RNA motifs with a central UAG trinucleotide with high affinity and specificity. The finding that MSI also promotes the replication of Zika virus, a neurotropic Flavivirus, has triggered further investigations of the biochemical principles behind MSI–RNA interactions. However, a detailed molecular understanding of the specificity of MSI RBD1/2 interaction with RNA is still missing. Here, we performed computational studies of MSI1–RNA association complexes, investigating different RNA pentamer motifs using molecular dynamics simulations with binding free energy calculations based on the solvated interaction energy method. Simulations with Alphafold2 suggest that predicted MS...

Research paper thumbnail of Effect of Water Microsolvation on the Excited-State Proton Transfer of 3-Hydroxyflavone Enclosed in γ-Cyclodextrin

Molecules, 2021

The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone... more The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone (3HF) and its inclusion complex with γ-cyclodextrin (γ-CD) was studied using computational approaches. From molecular dynamics simulations, two possible inclusion complexes formed by the chromone ring (C-ring, Form I) and the phenyl ring (P-ring, Form II) of 3HF insertion to γ-CD were observed. Form II is likely more stable because of lower fluctuation of 3HF inside the hydrophobic cavity and lower water accessibility to the encapsulated 3HF. Next, the conformation analysis of these models in the ground (S0) and the first excited (S1) states was carried out by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations, respectively, to reveal the photophysical properties of 3HF influenced by the γ-CD. The results show that the intermolecular hydrogen bonding (interHB) between 3HF and γ-CD, and intramolecular hydrogen bonding (intraHB) within 3HF are strengthened in the...

Research paper thumbnail of Accessible Charges in Structure-Activity Relationships. A Study on HEPT-based HIV-1 RT Inhibitors

Scientia Pharmaceutica, 2000

The solvent accessibility of charges is introduced in QSAR studies. Atomic charges which do have ... more The solvent accessibility of charges is introduced in QSAR studies. Atomic charges which do have contribution to the biological activity of a compound are more or less exposed to the environment (solvent), i.e. they have different possibilities to interact with biological macromolecules. Although one can imagine different ways in considering solvent accessibility, in this work it is taken into account by multiplying the net charge of an atom with its solvent accessible surface. To study the effect of accessibility of a charge on a biological activity, a large set (of 101) HEPT-based HIV- 1 reverse transcriptase (RT) inhibitors is analyzed, a molecu1a.r system, where the importance of electronic contribution is known. The results, based on multiple linear regression (MLR) and partial least squares (PLS) analysis, show that accessible charges correlate better with the RT inhibitory activity than net charges, leading to models with higher predictive ability.

Research paper thumbnail of Interactions of HLA-DR and Topoisomerase I Epitope Modulated Genetic Risk for Systemic Sclerosis

Scientific Reports, 2019

The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific a... more The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific alleles of human leukocyte antigen (HLA)-DR has been observed among various ethnics. The anti-Topoisomerase 1 antibody is a common autoantibody in SSc with diffuse cutaneous scleroderma, which is one of the clinical subtypes of SSc. On the other hand, an immunodominant peptide of topoisomerase 1 (Top1) self-protein (residues 349–368) was reported to have strong association with ATASSc. In this study, molecular dynamics simulation was performed on the complexes of Top1 peptide with various HLA-DR subtypes divided into ATASSc-associated alleles (HLA-DRB1*08:02, HLA-DRB1*11:01 and HLA-DRB1*11:04), suspected allele (HLA-DRB5*01:02), and non-associated allele (HLA-DRB1*01:01). The unique interaction for each system was compared to the others in terms of dynamical behaviors, binding free energies and solvation effects. Our results showed that three HLA-DR/Top1 complexes of ATASSc association mo...

Research paper thumbnail of Computational screening of chalcones acting against topoisomerase IIα and their cytotoxicity towards cancer cell lines

Journal of Enzyme Inhibition and Medicinal Chemistry, 2018

Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomera... more Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIa by computational techniques, and subsequently tested for their in vitro cytotoxicity. From the experimental IC 50 values, chalcone 3d showed a high cytotoxicity with IC 50 values of 10.8, 3.2 and 21.1 mM against the HT-1376, HeLa and MCF-7 cancer-derived cell lines, respectively, and also exhibited an inhibitory activity against hTopoIIa-ATPase that was better than the known inhibitor, salvicine. The observed ligand-protein interactions from a molecular dynamics study affirmed that 3d strongly interacts with the ATP-binding pocket residues. Altogether, the newly synthesised chalcone 3d has a high potential to serve as a lead compound for topoisomerase inhibitors.

Research paper thumbnail of Molecular recognition of naphthoquinone-containing compounds against human DNA topoisomerase IIα ATPase domain: A molecular modeling study

Journal of Molecular Liquids, 2017

Research paper thumbnail of Structural Analysis of Host–Guest Systems. Methyl-substituted Phenols in beta;-Cyclodextrin

Journal of Inclusion Phenomena

Complexation trajectories and the variation of induced circular dichroism are calculated for the ... more Complexation trajectories and the variation of induced circular dichroism are calculated for the docking of phenol and 2,4,6-trimethyl-phenol with-cyclodextrin. The results are compared to experimental chirality data to elucidate the mechanism of nonspecific molecular recognition processes in aqueous solution. Large geometrical changes along nearly isoenergetic Dynamic Monte Carlo trajectories show the conformational flexibility of such host-guest systems. This proves diffuse intermolecular interactions, van der Waals or electrostatic in nature, as the main contributions to the binding energy. The number and position of the methyl substituents of the guest reduces the complexity of the conformational space as the guest's position becomes fixed by steric constraints. The solvation free energy is calculated from the solvent accessible surface area weighted by respective atomic solvation parameters. Considering the solvation term in the dynamic simulations restricts the conformational flexibility of the macromolecular system. The relative importance of various contributions to the solvation energy is discussed and it is shown that those terms arising from the interaction of hydrophobic groups with the aqueous environment are essential for the determination of the complex structure. Considering these terms in the dynamic simulation model, the sign and strength of the calculated rotatory strength is in perfect agreement with induced circular dichroism obtained from experimentally determined averaged spectra. The results demonstrate the accuracy of the geometrical properties of host-guest systems obtained from these simulations.

Research paper thumbnail of Internally defined distances in 3D-quantitative structure-activity relationships

Journal of Computer-Aided Molecular Design

Research paper thumbnail of Predicting the Free Energies of Complexation Between Cyclodextrins and Guest Molecules: Linear versus Nonlinear Models

Pharmaceutical Research, 2000

Purpose. In the present paper, linear and nonlinear models forcomplexation of a- ß- and ?-cyclode... more Purpose. In the present paper, linear and nonlinear models forcomplexation of a- ß- and ?-cyclodextrin with guest molecules are developed,with the aim of free energy prediction and interpretation of theassociation process.

Research paper thumbnail of Influence of solvation on helix formation of poly-alanine studied by multiple annealing simulations

Journal of Molecular Structure: THEOCHEM, 1996

The influence of solvation on a-helix formation is studied for a 14-residue homoalanine and a 16-... more The influence of solvation on a-helix formation is studied for a 14-residue homoalanine and a 16-residue alanine-based polypeptide, in aqueous solution. Four variants of Dynamic Monte Carlo @MC) simulations, using a multiple annealing procedure are performed. The results obtained under in vacua conditions are compared to simulations considering either contributions to the solvation energy of non-favourable solvent interactions by hydrophobic groups, or the total solvation energy, both calculated by a continuum approximation. The highest average helix lengths are found when the total solvation energy (hydrophilic and hydrophobic contributions) is considered, although solvation counteracts the formation of compact peptide structures. The influence of solvation on helix formation is discussed.

Research paper thumbnail of A Method for Predicting the Free Energies of Complexation between β-Cyclodextrin and Guest Molecules

Journal of Inclusion Phenomena and Macrocyclic Chemistry - J INCL PHENOM MACROCYCL CHEM, 2000

In the present work, linear regression models for theprediction of the free energies of complexat... more In the present work, linear regression models for theprediction of the free energies of complexationbetween guest molecules and ß-cyclodextrin arededuced. For 70 compounds (mostly pharmaca), theexperimentally determined 1 : 1 stability constants aretransformed into the respective free energies, whichare then correlated with molecular descriptors.

Research paper thumbnail of Molecular dynamics simulations and quantum chemical calculations on β-cyclodextrin spironolactone complex

Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2007

Molecular dynamics simulations on b-cyclodextrin in vacuo, with water and complexed with spironol... more Molecular dynamics simulations on b-cyclodextrin in vacuo, with water and complexed with spironolactone (SP) were performed at a temperature of 300 K over a period of 1 ns. Two different orientations of SP in the cavity were considered. Along with conformational parameters, the formation of hydrogen bonds has been monitored during the whole simulation time. Cyclodextrins have the capability to form hydrogen bonds with the surrounding water molecules or intramolecular ones. The incorporation of ligands into the hydrophobic interior of b-cyclodextrin changes the preference of hydrogen bonds significantly and results in a contribution to the decrease of flexibility. Quantum chemical calculations on SP-b-CD inclusion complex were performed to determine the interaction energy and to prove the applicability of various methods. Although all applied methods describe reasonable geometries for the association complex, higher level methods (e.g., B3LYP/6-31G(d,p)) seem to be necessary to determine reliable interaction energies.

Research paper thumbnail of Threshold-Based Structure−Activity Relationships of Pyrazines with Bell-Pepper Flavor

Journal of Agricultural and Food Chemistry, 2000

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (Co... more Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Research paper thumbnail of Theoretical study on the intramolecular hydrogen bond in chloro-substituted N,N-dimethylaminomethylphenols. I. Structural effects

Journal of Molecular Structure, Aug 1, 2004

Ab initio and density functional calculations are applied to study the influence of an increasing... more Ab initio and density functional calculations are applied to study the influence of an increasing number of chlorine substituents on the properties of the intramolecular hydrogen bond in substituted Mannich bases. It is shown, that not only the acidity of the proton donor, which depends on the number of chlorine atoms at the aromatic ring, but also steric interactions modify the geometry of the hydrogen bond. Specific interactions of O-Cl• • •H-O hydrogen-bonding in some derivatives are estimated by calculations on related chlorophenols.