16 research outputs found
Theoretical Model of EphA2-Ephrin A1 Inhibition
This work aims at the theoretical description of EphA2-ephrin A1 inhibition by small molecules. Recently proposed ab initio-based scoring models, comprising long-range components of interaction energy, is tested on lithocholic acid class inhibitors of this protein–protein interaction (PPI) against common empirical descriptors. We show that, although limited to compounds with similar solvation energy, the ab initio model is able to rank the set of selected inhibitors more effectively than empirical scoring functions, aiding the design of novel compounds
Physical nature of intermolecular interactions within cAMP-dependent protein kinase active site: Differential transition state stabilization in phosphoryl transfer reaction
Alkaline Hydrolysis of Organophosphorus Pesticides: The Dependence of the Reaction Mechanism on the Incoming Group Conformation
The fundamental mechanism of organophosphate
hydrolysis is the
subject of a growing interest resulting from the need for safe disposal
of phosphoroorganic pesticides. Herein, we present a detailed ab initio
study of the gas-phase mechanisms of alkaline hydrolysis of PâO
and PâS bonds in a number of organophosphorus pesticides, including
paraoxon, methyl parathion, fenitrothion, demeton-S, acephate, phosalone,
azinophos-ethyl, and malathion. Our main finding is that the incoming
group conformation influences the mechanism of decomposition of organophosphate
and organothiophosphate compounds. Depending on the orientation of
the attacking nucleophile, hydrolysis reaction might follow either
a multistep pathway characterized by the presence of a pentavalent
intermediate or a one-step mechanism proceeding through a single transition
state. Despite a widely accepted view of the phosphotriester PâO
bonds being decomposed exclusively via a direct-displacement mechanism,
the occurrence of alternative, qualitatively distinct reaction pathways
was confirmed for alkaline hydrolysis of both PâO and PâS
bonds. As the pesticides included in our quantum chemical analysis
involve organophosphate, phosphorothioate, and phosphorodithioate
compounds, the influence of oxygen to sulfur substitution on the structural
and energetic characteristics of the hydrolysis pathway is also discussed
Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug
A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues
Rational Design of Orthogonal Multipolar Interactions with Fluorine in ProteinâLigand Complexes
Synthesis, structural characterization, docking simulation and in vitro antiproliferative activity of the new gold(III) complex with 2-pyridineethanol
Physical Nature of Fatty Acid Amide Hydrolase Interactions with Its Inhibitors: Testing a Simple Nonempirical Scoring Model
Fatty
acid amide hydrolase (FAAH) is an enzyme responsible for
the deactivating hydrolysis of fatty acid ethanolamide neuromodulators.
FAAH inhibitors have gained considerable interest due to their possible
application in the treatment of anxiety, inflammation, and pain. In
the context of inhibitor design, the availability of reliable computational
tools for predicting binding affinity is still a challenging task,
and it is now well understood that empirical scoring functions have
several limitations that in principle could be overcome by quantum
mechanics. Herein, systematic ab initio analyses of FAAH interactions
with a series of inhibitors belonging to the class of the <i>N</i>-alkylcarbamic acid aryl esters have been performed. In
contrast to our earlier studies of other classes of enzymeâinhibitor
complexes, reasonable correlation with experimental results required
us to consider correlation effects along with electrostatic term.
Therefore, the simplest comprehensive nonempirical model allowing
for qualitative predictions of binding affinities for FAAH ligands
consists of electrostatic multipole and second-order dispersion terms.
Such a model has been validated against the relative stabilities of
the benchmark S66 set of biomolecular complexes. As it does not involve
parameters fitted to experimentally derived data, this model offers
a unique opportunity for generally applicable inhibitor design and
virtual screening
Tracking molecular charge distribution along reaction paths with atomic multipole moments
Rational Design of Orthogonal Multipolar Interactions with Fluorine in ProteinâLigand Complexes
Multipolar interactions involving
fluorine and the protein backbone
have been frequently observed in proteinâligand complexes.
Such fluorineâbackbone interactions may substantially contribute
to the high affinity of small molecule inhibitors. Here we found that
introduction of trifluoromethyl groups into two different sites in
the thienopyrimidine class of meninâMLL inhibitors considerably
improved their inhibitory activity. In both cases, trifluoromethyl
groups are engaged in short interactions with the backbone of menin.
In order to understand the effect of fluorine, we synthesized a series
of analogues by systematically changing the number of fluorine atoms,
and we determined high-resolution crystal structures of the complexes
with menin. We found that introduction of fluorine at favorable geometry
for interactions with backbone carbonyls may improve the activity
of meninâMLL inhibitors as much as 5- to 10-fold. In order
to facilitate the design of multipolar fluorineâbackbone interactions
in proteinâligand complexes, we developed a computational algorithm
named FMAP, which calculates fluorophilic sites in proximity to the
protein backbone. We demonstrated that FMAP could be used to rationalize
improvement in the activity of known protein inhibitors upon introduction
of fluorine. Furthermore, FMAP may also represent a valuable tool
for designing new fluorine substitutions and support ligand optimization
in drug discovery projects. Analysis of the meninâMLL inhibitor
complexes revealed that the backbone in secondary structures is particularly
accessible to the interactions with fluorine. Considering that secondary
structure elements are frequently exposed at protein interfaces, we
postulate that multipolar fluorineâbackbone interactions may
represent a particularly attractive approach to improve inhibitors
of proteinâprotein interactions
Rational Design of Orthogonal Multipolar Interactions with Fluorine in ProteinâLigand Complexes
Multipolar interactions involving
fluorine and the protein backbone
have been frequently observed in proteinâligand complexes.
Such fluorineâbackbone interactions may substantially contribute
to the high affinity of small molecule inhibitors. Here we found that
introduction of trifluoromethyl groups into two different sites in
the thienopyrimidine class of meninâMLL inhibitors considerably
improved their inhibitory activity. In both cases, trifluoromethyl
groups are engaged in short interactions with the backbone of menin.
In order to understand the effect of fluorine, we synthesized a series
of analogues by systematically changing the number of fluorine atoms,
and we determined high-resolution crystal structures of the complexes
with menin. We found that introduction of fluorine at favorable geometry
for interactions with backbone carbonyls may improve the activity
of meninâMLL inhibitors as much as 5- to 10-fold. In order
to facilitate the design of multipolar fluorineâbackbone interactions
in proteinâligand complexes, we developed a computational algorithm
named FMAP, which calculates fluorophilic sites in proximity to the
protein backbone. We demonstrated that FMAP could be used to rationalize
improvement in the activity of known protein inhibitors upon introduction
of fluorine. Furthermore, FMAP may also represent a valuable tool
for designing new fluorine substitutions and support ligand optimization
in drug discovery projects. Analysis of the meninâMLL inhibitor
complexes revealed that the backbone in secondary structures is particularly
accessible to the interactions with fluorine. Considering that secondary
structure elements are frequently exposed at protein interfaces, we
postulate that multipolar fluorineâbackbone interactions may
represent a particularly attractive approach to improve inhibitors
of proteinâprotein interactions