Ensemble Docking as a Tool for the Rational Design of Peptidomimetic Sortase A Inhibitors.

Sortase A (SrtA) of has long been shown to be a relevant molecular target for antibacterial development. Moreover, the designed SrtA inhibitors act via the antivirulence mechanism, potentially causing less evolutional pressure and reduced antimicrobial resistance. However, no marketed drugs or even drug candidates have been reported until recently, despite numerous efforts in the field.

In silico studies of the open form of human tissue transglutaminase.

Human tissue transglutaminase (tTG) is an intriguing multifunctional enzyme involved in various diseases, including celiac disease and neurological disorders. Although a number of tTG inhibitors have been developed, the molecular determinants governing ligand binding remain incomplete due to the lack of high-resolution structural data in the vicinity of its active site. In this study, we obtained the complete high-resolution model of tTG by in silico methods based on available PDB structures.

Do electrostatic interactions make a difference in physics-based AutoDock4 scoring function?

Physics-based scoring function AutoDock4 is one of the most successfully applied tools in the area of structure-based drug design. However, current scoring functions are still far from being perfect. In a recent work highlighting the strengths and deficiencies of current scoring functions, we discovered that the residual error of ΔG predictions made by AutoDock4 is highly correlated to the presence of formally charged fragments in a ligand.

On hidden anisotropy of formally charged fragments.

The proper and precise reproduction of the molecular electrostatic potential (MEP) is crucial to describe correctly electrostatic interactions in molecular modeling. Most of the classical molecular mechanics force fields for biomolecules and drug-like molecules use the atom-centered point charges to describe MEP. However, it has been systematically pointed out in literature that such an approximation is not always enough, and some groups, like amino group or heavy halogens, require the use of anisotropic model for better description of their MEP.

Theoretical Studies of Leu-Pro-Arg-Asp-Ala Pentapeptide (LPRDA) Binding to Sortase A of .

Sortase A (SrtA) of is a well-defined molecular target to combat the virulence of these clinically important bacteria. However up to now no efficient drugs or even clinical candidates are known, hence the search for such drugs is still relevant and necessary. SrtA is a complex target, so many straight-forward techniques for modeling using the structure-based drug design (SBDD) fail to produce the results they used to bring for other, simpler, targets.

Assessing How Residual Errors of Scoring Functions Correlate to Ligand Structural Features.

Scoring functions (SFs) are ubiquitous tools for early stage drug discovery. However, their accuracy currently remains quite moderate. Despite a number of successful target-specific SFs appearing recently, up until now, no ideas on how to systematically improve the general scope of SFs have been formulated.

Is an Inductive Effect Explicit Account Required for Atomic Charges Aimed at Use within the Force Fields?

Polarization and inductive effects are the concepts that have been widely used in qualitative and even quantitative descriptions of experimentally observed properties in chemistry. The polarization effect has proven to be important in cases of biomolecular modeling though still the vast majority of molecular simulations use the classical non-polarizable force fields. In the last few decades, a lot of effort has been put into promoting the polarization effect and incorporating it into modern force fields and charge calculation methods.

Investigation of the tight binding mechanism of a new anticoagulant DD217 to factor Xa by means of molecular docking and molecular dynamics.

A new promising drug candidate DD217 has been proposed recently as a potent anticoagulant acting on factor Xa (fXa) target. It exhibits the lowest concentration of doubling the prothrombin time among the known anticoagulants. In order to explain the efficacy of DD217 in terms of molecular interactions with its target we studied the hypothesis of the tight binding mechanism by means of molecular dynamics simulations and statistical analysis of the trajectory.

In Silico Structure-Based Approach for Group Efficiency Estimation in Fragment-Based Drug Design Using Evaluation of Fragment Contributions.

The notion of a contribution of a specific group in an organic molecule's property and/or activity is both common in our thinking and is still not strictly correct due to the inherent non-additivity of free energy with respect to molecular fragments composing a molecule. The fragment- based drug discovery (FBDD) approach has proven to be fruitful in addressing the above notions. The main difficulty of the FBDD, however, is in its reliance on the low throughput and expensive experimental means of determining the fragment-sized molecules binding.

Selection of Promising Novel Fragment Sized SrtA Noncovalent Inhibitors Based on QSAR and Docking Modeling Studies.

Sortase A (SrtA) of has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used.

Computational characterization of the glutamate receptor antagonist perampanel and its close analogs: density functional exploration of conformational space and molecular docking study.

Perampanel approved by FDA in 2012 is a first-in-class antiepileptic drug which inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents. It is markedly more active than many of its close analogs, and the reasons for this activity difference are not quite clear. Recent crystallographic studies allowed the authors to identify the location of its binding site.

Iterative Solvers for Empirical Partial Atomic Charges: Breaking the Curse of Cubic Numerical Complexity.

Rational drug design involves a vast amount of computations to get thermodynamically reliable results and often relies on atomic charges as a means to model electrostatic interactions within the system. Computational inefficiency often hampers the development of new and wider dissemination of the known methods; thus, any source to speed up the calculations without a sacrifice in quality is warranted. At the heart of many empirical methods of calculating atomic charges is the solution of a system of linear algebraic equations (SLAE).

Quadrupole Correction: From Molecular Electrostatic Potential to Free Energies of Halogen Bonding.

Recently several molecular mechanics models of halogen bonding have been published. They describe the electrostatic potential anisotropy near the heavy halogen atom (known as a σ-hole) in different ways, ranging from an all-atom multipole expansion to a single positive extra-point charge. However, the question of a reasonable balance between the accuracy and the simplicity of the model remains open.

Solving 3-D PDEs by Tensor B-Spline Methodology: A High Performance Approach Applied to Optical Diffusion Tomography.

Solutions of 3-D elliptic PDEs form the basis of many mathematical models in medicine and engineering. Solving elliptic PDEs numerically in 3-D with fine discretization and high precision is challenging for several reasons, including the cost of 3-D meshing, the massive increase in operation count, and memory consumption when a high-order basis is used, and the need to overcome the "curse of dimensionality." This paper describes how these challenges can be either overcome or relaxed by a Tensor B-spline methodology with the following key properties: 1) the tensor structure of the variational formulation leads to regularity, separability, and sparsity, 2) a method for integration over the complex domain boundaries eliminates meshing, and 3) the formulation induces high-performance and memory-efficient computational algorithms.

Elastic, dipole-dipole interaction and viscosity impact on vibrational properties of anisotropic hexagonal microtubule lattice.

The paper investigates microtubules lattice properties taking into consideration elastic, dipole-dipole interaction of tubulins and viscosity. A microtubule is modeled as a system of bound tubulins, forming a skewed hexagonal two-dimensional lattice. Wave frequencies and group velocities have been calculated.

Multipole models of sulphur for accurate anisotropic electrostatic interactions within force fields.

Nowadays, as computing has become much more available, a fresh momentum has been observed in the field of re-visioning and re-parameterizing the usual tools, as well as estimating for the incorporation of new qualitative capabilities, aimed at making more accurate and reliable predictions in drug discovery processes. Inspired by the success of modelling the electrostatic part of the halogen bonding (XB) by means of the distributed multipole expansion, a study is presented which attempts to extend this approach to a tougher case of σ-hole interaction: sulphur-based chalcogen bonding. To that end, 11 anisotropic models have been derived and tested for their performance in the reproduction of reference ab initio molecular electrostatic potential.

A Tensor B-Spline Approach for Solving the Diffusion PDE With Application to Optical Diffusion Tomography.

Optical Diffusion Tomography (ODT) is a modern non-invasive medical imaging modality which requires mathematical modelling of near-infrared light propagation in tissue. Solving the ODT forward problem equation accurately and efficiently is crucial. Typically, the forward problem is represented by a Diffusion PDE and is solved using the Finite Element Method (FEM) on a mesh, which is often unstructured.

Use of Piezoelectric Immunosensors for Detection of Interferon-Gamma Interaction with Specific Antibodies in the Presence of Released-Active Forms of Antibodies to Interferon-Gamma.

In preliminary ELISA studies where released-active forms (RAF) of antibodies (Abs) to interferon-gamma (IFNg) were added to the antigen-antibody system, a statistically significant difference in absorbance signals obtained in their presence in comparison to placebo was observed. A piezoelectric immunosensor assay was developed to support these data and investigate the effects of RAF Abs to IFNg on the specific interaction between Abs to IFNg and IFNg. The experimental conditions were designed and optimal electrode coating, detection circumstances and suitable chaotropic agents for electrode regeneration were selected.

Perspectives of Halogen Bonding Description in Scoring Functions and QSAR/QSPR: Substituent Effects in Aromatic Core.

Halogen bonding (XB) is a new promising interaction pattern in medicinal chemistry. It has predominantly electrostatic nature - high electrostatic potential anisotropy. However to fully unleash the potential of XB in rational drug design fast and robust empirical methods of XB description should be developed.

Simulation of intramolecular hydrogen bond dynamics in manzamine A as a sensitive test for charge distribution quality.

Subtle balance of inter- and intramolecular hydrogen bond strength in aqueous solutions often governs the structure and dynamics of molecular species used as potential drugs and in supramolecular applications. In silico molecular dynamics study of water solution of manzamine A has been performed with different atomic charges in order to investigate the influence of charge distribution choice on predicting qualitative and quantitative features of the simulated systems. Various well known charge schemes (MK-ESP, RESP, Mulliken, AMI-BCC, Gasteiger-Hückel, Gasteiger-Marsili, MMFF94, and Dynamic Electronegativity Relaxation - DENR) led to qualitatively different pictures of dynamic behavior of the intramolecular hydrogen bond.

General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors.

Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem.

Fast tools for calculation of atomic charges well suited for drug design.

Two novel approaches to construct empirical schemes for partial atomic charge calculation were proposed. The charge schemes possess important benefits. First, they produce both topologically symmetrical and environment dependent charges.