Does the SARS-CoV-2 Spike Receptor-Binding Domain Hamper the Amyloid Transformation of Alpha-Synuclein after All?

Interactions of key amyloidogenic proteins with SARS-CoV-2 proteins may be one of the causes of expanding and delayed post-COVID-19 neurodegenerative processes. Furthermore, such abnormal effects can be caused by proteins and their fragments circulating in the body during vaccination. The aim of our work was to analyze the effect of the receptor-binding domain of the coronavirus S-protein domain (RBD) on alpha-synuclein amyloid aggregation.

Inhibition of SYK and cSrc kinases can protect bone and cartilage in preclinical models of osteoarthritis and rheumatoid arthritis.

The pathophysiology of osteoarthritis (OA) includes the destruction of subchondral bone tissue and inflammation of the synovium. Thus, an effective disease-modifying treatment should act on both of these pathogenetic components. It is known that cSrc kinase is involved in bone and cartilage remodeling, and SYK kinase is associated with the inflammatory component.

Comparison of Methods for Bulk Automated Simulation of Glycosidic Bond Conformations.

Six empirical force fields were tested for applicability to calculations for automated carbohydrate database filling. They were probed on eleven disaccharide molecules containing representative structural features from widespread classes of carbohydrates. The accuracy of each method was queried by predictions of nuclear Overhauser effects (NOEs) from conformational ensembles obtained from 50 to 100 ns molecular dynamics (MD) trajectories and their comparison to the published experimental data.

Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity.

The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin embryo model.

Structure-based inhibitors targeting the alpha-helical domain of the Spiroplasma melliferum histone-like HU protein.

Here we report bisphenol derivatives of fluorene (BDFs) as a new type of chemical probes targeting a histone-like HU protein, a global regulator of bacterial nucleoids, via its dimerization interface perturbation. BDFs were identified by virtual screening and molecular docking that targeted the core of DNA-binding β-saddle-like domain of the HU protein from Spiroplasma melliferum. However, NMR spectroscopy, complemented with molecular dynamics and site-directed mutagenesis, indicated that the actual site of the inhibitors' intervention consists of residues from the α-helical domain of one monomer and the side portion of the DNA-binding domain of another monomer.

Novel curcumin derivatives as P-glycoprotein inhibitors: Molecular modeling, synthesis and sensitization of multidrug resistant cells to doxorubicin.

The MDR1/P-glycoprotein (Pgp)/ABCB1 multidrug transporter is being investigated as a druggable target for antitumor therapy for decades. The natural product curcumin is known to provide an efficient scaffold for compounds capable of blocking Pgp mediated efflux and sensitization of multidrug resistant (MDR) cells to the Pgp transported drug doxorubicin (Dox). We performed molecular dynamics simulations and docking of curcumin derivatives into the Pgp model.

Inhibition of Prion Propagation by 3,4-Dimethoxycinnamic Acid.

Neurodegenerative diseases are associated with accumulation of amyloid-type protein misfolding products. Prion protein (PrP) is known for its ability to aggregate into soluble oligomers that in turn associate into amyloid fibrils. Preventing the formation of these infective and neurotoxic entities represents a viable strategy to control prion diseases.

An explicit account of solvation is essential for modeling Suzuki-Miyaura coupling in protic solvents.

We compared explicit and implicit solvation approaches in modeling the free energy profile of the final step of Suzuki-Miyaura coupling. Both approaches produced similar ΔG(≠) in all the studied solvents (benzene, toluene, DMF, ethanol, and water). Solvation free energies of individual reaction components reasonably correlated for explicit and implicit models in aprotic solvents (RMSE = 30-50 kJ mol(-1), R(2) > 0.

PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation.

Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I.

2,3-Dihydroxy-quinoxaline induces ATPase activity of Herpes Simplex Virus thymidine kinase.

2,3-Dihydroxy-quinoxaline, a small molecule that promotes ATPase catalytic activity of Herpes Simplex Virus thymidine kinase (HSV-TK), was identified by virtual screening. This compound competitively inhibited HSV-TK catalyzed phosphorylation of acyclovir with Ki=250 μM (95% CI: 106-405 μM) and dose-dependently increased the rate of the ATP hydrolysis with KM=112 μM (95% CI: 28-195 μM). The kinetic scheme consistent with this experimental data is proposed.

Alchemical FEP Calculations of Ligand Conformer Focusing in Explicit Solvent.

Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of "focusing" on one specific conformational state that binds to a protein.

Lead Finder docking and virtual screening evaluation with Astex and DUD test sets.

Lead Finder is a molecular docking software. Sampling uses an original implementation of the genetic algorithm that involves a number of additional optimization procedures. Lead Finder's scoring functions employ a set of semi-empiric molecular mechanics functionals that have been parameterized independently for docking, binding energy predictions and rank-ordering for virtual screening.

Hit clustering can improve virtual fragment screening: CDK2 and PARP1 case studies.

Virtual fragment screening could be a promising alternative to existing experimental screening techniques. However, reliable methods of in silico fragment screening are yet to be established and validated. In order to develop such an approach we first checked how successful the existing molecular docking methods can be in predicting fragment binding affinities and poses.

TSAR, a new graph-theoretical approach to computational modeling of protein side-chain flexibility: modeling of ionization properties of proteins.

A new graph-theoretical approach called thermodynamic sampling of amino acid residues (TSAR) has been elaborated to explicitly account for the protein side chain flexibility in modeling conformation-dependent protein properties. In TSAR, a protein is viewed as a graph whose nodes correspond to structurally independent groups and whose edges connect the interacting groups. Each node has its set of states describing conformation and ionization of the group, and each edge is assigned an array of pairwise interaction potentials between the adjacent groups.

CSAR scoring challenge reveals the need for new concepts in estimating protein-ligand binding affinity.

The dG prediction accuracy by the Lead Finder docking software on the CSAR test set was characterized by R(2)=0.62 and rmsd=1.93 kcal/mol, and the method of preparation of the full-atom structures of the test set did not significantly affect the resulting accuracy of predictions.

Improving performance of docking-based virtual screening by structural filtration.

In the current study an innovative method of structural filtration of docked ligand poses is introduced and applied to improve the virtual screening results. The structural filter is defined by a protein-specific set of interactions that are a) structurally conserved in available structures of a particular protein with its bound ligands, and b) that can be viewed as playing the crucial role in protein-ligand binding. The concept was evaluated on a set of 10 diverse proteins, for which the corresponding structural filters were developed and applied to the results of virtual screening obtained with the Lead Finder software.

Developing novel approaches to improve binding energy estimation and virtual screening: a PARP case study.

Poly-(ADP-ribose)-polymerase (PARP) is a promising anti-cancer target as it plays a crucial role in the cellular reparation and survival mechanisms. However, the development of a robust and cost effective experimental technique to screen PARP inhibitors is still a scientific challenge owing to the difficulties in quantitative detection of the enzyme activity. In this work we demonstrate that the computational chemistry tools including molecular docking and scoring can perform on par with the experimental studies in assessing binding constants and in the recovery of active compounds in virtual screening.

Lead finder: an approach to improve accuracy of protein-ligand docking, binding energy estimation, and virtual screening.

An innovative molecular docking algorithm and three specialized high accuracy scoring functions are introduced in the Lead Finder docking software. Lead Finder's algorithm for ligand docking combines the classical genetic algorithm with various local optimization procedures and resourceful exploitation of the knowledge generated during docking process. Lead Finder's scoring functions are based on a molecular mechanics functional which explicitly accounts for different types of energy contributions scaled with empiric coefficients to produce three scoring functions tailored for (a) accurate binding energy predictions; (b) correct energy-ranking of docked ligand poses; and (c) correct rank-ordering of active and inactive compounds in virtual screening experiments.