A5065224837- Crystallography and molecular interactions
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Computational Drug Discovery Methods
- Advanced Chemical Physics Studies
- Protein Structure and Dynamics
- Inorganic Fluorides and Related Compounds
- Nitric Oxide and Endothelin Effects
- Spectroscopy and Quantum Chemical Studies
- Chemical Thermodynamics and Molecular Structure
- Peptidase Inhibition and Analysis
- DNA and Nucleic Acid Chemistry
- Molecular spectroscopy and chirality
- Metal and Thin Film Mechanics
- Ubiquitin and proteasome pathways
- Aldose Reductase and Taurine
- Monoclonal and Polyclonal Antibodies Research
- Bacterial Genetics and Biotechnology
- Eicosanoids and Hypertension Pharmacology
- Cancer therapeutics and mechanisms
- Structural and Chemical Analysis of Organic and Inorganic Compounds
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Crystallization and Solubility Studies
- Machine Learning in Materials Science
University of Chemistry and Technology, Prague
2020-2024
Max Planck Institute for Multidisciplinary Sciences
2022-2023
Max Planck Institute for Biophysical Chemistry
2020-2021
Max Planck Society
2020
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2007-2017
Forschungszentrum Jülich
2014-2017
Czech Academy of Sciences
2010-2015
German Research School for Simulation Sciences
2014
Charles University
2012-2013
Contipro (Czechia)
2012
Until recently, the description of halogen bonding by standard molecular mechanics has been poor, owing to lack so-called σ hole localized at halogen. This region positive electrostatic potential located on top a atom explains counterintuitive attraction halogenated compounds interacting with Lewis bases. In mechanics, is modeled massless point charge attached and referred as an explicit (ESH). Here, we introduce compare three methods ESH construction, which differ in complexity input...
The σ-holes of halogen atoms on various aromatic scaffolds were described in terms their size and magnitude. electrostatic potential maps at the CAM-B3LYP-D3(bj)/def2-QZVP level calculated more than 100 analogues thoroughly analysed to relate binding preferences halogenated compounds. Both magnitude σ-hole increase when passing from chlorinated iodinated analogues. Also, properties studied upon chemical substitution ring as well ring. Further, angular variations interactions investigated a...
In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The was derived from known AR binder, which had previously been shown to form halogen bond between its bromine atom and the oxygen Thr-113 side chain AR. series, strength modulated by two factors, namely bromine–iodine substitution fluorination aromatic ring in several positions. role single AR–ligand binding elucidated advanced free energy calculations involving semiempirical quantum chemical Hamiltonian....
Abstract This Minireview discusses the latest developments in modern quantum mechanics (QM)‐based computer‐aided drug design, especially using semiempirical QM (SQM) methods. It first tackles biochemical and biophysical quantities approaches to their measurements. Protein–ligand affinities are determined mostly by noncovalent interactions. The text thus illustrates how these can be accurately treated with SQM Next, a construction of SQM‐based scoring function is presented its applications...
A novel approach in molecular docking was successfully used to reproduce protein–ligand experimental geometries. When dealing with halogenated compounds the correct description of halogen bonds between ligand and protein is shown be essential. Applying a simple mechanistic model for improved geometries as well bond features, which makes it promising tool future computer-aided drug development.
The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles conformations in water water-saturated octanol. energies calculated by popular models based quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well molecular (MM) point-charge (GB, PB). the was tested comparison with experimental water–octanol transfer (ΔGow) using single-...
Halogen bonding (X-bonding) has attracted notable attention among noncovalent interactions. This highly directional attraction between a halogen atom and an electron donor been exploited in knowledge-based drug design. A great deal of information gathered about X-bonds protein–ligand complexes, as opposed to nucleic acid complexes. Here we provide thorough analysis complexes containing either halogenated building blocks or ligands. We analyzed close contacts halogens electron-rich moieties....
The effect of polar flattening on the stability 32 halogen-bonded complexes was investigated by utilizing CCSD(T)/CBS, DFT, and DFT-SAPT/CBS methods. It is shown that value increases with decreasing studied isodensity. For investigated, based isodensity 0.001 au reaches 0.2-0.3 Å 10-15% in absolute relative values, respectively. These geometrical changes induce differences stabilization energy up to 20%.
The effect of halogen-to-hydrogen bond substitution on the binding energetics and biological activity a human aldose reductase inhibitor has been studied using X-ray crystallography, IC50 measurements, advanced free energy calculations, simulations. replacement Br or I atoms by an amine (NH2) group not induced changes in original geometry complex, which made it possible to study isolated features selected noncovalent interactions biomolecular complex.
A DNA dodecamer and the methyladenine···methylthymine (mA···mT) complex in aqueous environment have been studied by means of molecular dynamics simulation, with a modified force field accounting for hypothetical absence London dispersion forces. Under these conditions, mA···mT is preserved, while double-helical oligomer passes via an extended, ladder-like intermediate to collapsed structure. The results are interpreted terms stability specificity structure complexes. While hydrophobic effect...
The structure of the phenol dimer and phenol...methanol complexes was determined by gradient optimization using Hartree-Fock (HF), MP2, DFT, RI-DFT-D methods with various basis sets. Theoretical rotational constants were compared experimental values following conclusions made: (1) HF DFT fail to predict cluster geometries; (2) MP2 a medium set yields reliable geometries but only because compensation for errors; (3) when AO is enlarged, geometry becomes incorrect, theoretical higher...
The ribosome is a fundamental biomolecular complex that synthesizes proteins in cells. Nascent emerge from the through tunnel, where they may interact with tunnel walls or small molecules such as antibiotics. These interactions can cause translational arrest notable physiological consequences. Here, we studied caused by regulatory peptide VemP, which known to form α-helices inside near peptidyl transferase center under specific conditions. We used all-atom molecular dynamics simulations of...
Abstract The reliability of the AMBER force field is tested by comparing total interaction energy and dispersion with reference data obtained at density functional theory–symmetry‐adapted perturbation treatment (DFT–SAPT)/aug‐cc‐pVDZ level. comparison made for 194 different geometries noncovalent complexes (H‐bonded, stacked, mixed, dispersion‐bound), equilibrium distances as well longer (up to a relative distance two). energies agree very only strength H‐bonded slightly underestimated. In...
We investigated the intercalation of an antitumor drug ellipticine into four adenine−thymine (AT) rich DNA duplexes with focus on configurational entropy, by means molecular dynamics (MD) simulations. Two possible binding orientations in a double helix were studied, and orientation pyrrole nitrogen exposed major groove was identified as more probable. The entropy change is shown to contribute significantly free energy. magnitude this contribution depends exact sequence. A detailed analysis...
Various cluster models of graphene and a periodic with two organic electron acceptors (tetracyanoethylene tetracyanoquinodimethane) were investigated by means several quantum chemical molecular mechanical approaches. The benchmark interaction energies the coronene complexes calculated at MP2.5/CBS/6-31G*(0.25) level theory. SCS-MI-MP2, BLYP-D3 and, surprisingly, also AMBER showed modest agreement in absolute as well relative energies. Consequently, larger these lower levels theory including...
Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 well characterized high retinaldehyde activity, involved in the development of several cancer types, enzymatic activity and physiological role AKR1B15 are still poorly known. Here, purified recombinant has been subjected to substrate specificity characterization, kinetic analysis inhibitor screening, combined structural modeling. active towards...
To contribute to the understanding of noncovalent binding halogenated molecules with a biological activity, electrostatic potential (ESP) maps more than 2,500 compounds were thoroughly analysed. A peculiar region positive ESP, called $σ$-hole, is concept central importance for halogen bonding. We aim at simplifying view on $σ$-holes and provide general trends in organic drug-like molecules. The results are fair agreement crystallographic surveys small as well biomolecular complexes attempt...
In this study, an extensive sampling of the conformational space nine HIV-1 protease inhibitors was performed to estimate uncertainty with which a single-conformation scoring scheme approximates ligand−protein binding free energy. The SMD implicit solvation/desolvation energy and gas-phase PM6-DH2 were calculated for set 1600 conformations each ligand. probability density functions energies compared values obtained from approach short ab initio molecular dynamics simulation. relative in...