Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates.

The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB).

Behavior of uncharged oximes compared to HI6 and 2-PAM in the human AChE-tabun conjugate: a molecular modeling approach.

Tabun is one of the most dangerous nerve agents because it has deleterious effects like inhibition of the essential enzymes acetylcholinesterase (AChE) and butyrylcholinesterase. Some oximes such HI6 as 2-PAM are nucleophiles that are capable to reactivate inhibited human AChE under some conditions. Zwitterionic and cationic species have the best chance of productive action on inhibited AChE.

Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors.

Molecular dynamics (MD) simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) were carried out for up to 20-40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket.

Dynamical study, hydrogen bond analysis, and constant pH simulations of the beta carbonic anhydrase of Methanobacterium thermoautotrophicum.

Within the five classes (α, β, γ, δ, and ζ) of carbonic anhydrases (CAs) the first two, containing mammal and plant representatives, are the most studied among all CAs. In this study, we have focused our investigation on the beta-class carbonic anhydrase of Methanobacterium thermoautotrophicum. We investigated both the importance of the Asp-Arg dyad near the catalytic zinc-bound water and the possible roles that water molecules within the active site and residues near the entrance of the catalytic cleft have on the first step of the enzyme's reaction mechanism.

Hologram QSAR models of a series of 6-arylquinazolin-4-amine inhibitors of a new Alzheimer's disease target: dual specificity tyrosine-phosphorylation-regulated kinase-1A enzyme.

Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer's disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.

A versatile low temperature solid-state synthesis of vanadium nitride (VN) via a "guanidinium-route": experimental and theoretical studies from the key-intermediate to the final product.

An easy and efficient method ("guanidinium route") to synthesize vanadium nitride (VN) is evaluated in this paper. Initially, ammonium m-vanadate was mixed with guanidinium carbonate, producing an important intermediate, ammonium m-vanadate (GmV), through a solid-state reaction. GmV was decomposed as a function of the temperature and studied with TGA, DRX, FT-Infrared, Temperature-Programmed Surface Reaction (TPSR) and DFT.

Residue-ligand interaction energy (ReLIE) on a receptor-dependent 3D-QSAR analysis of S- and NH-DABOs as non-nucleoside reverse transcriptase inhibitors.

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by receptor-dependent (RD) three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to derive RD-3D-QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue) simulated by molecular dynamics, an approach named Residue-Ligand Interaction Energy (ReLIE). This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference.

Application of 4D-QSAR studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators.

Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.

Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE).

Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A-F (N = 47, q(2) = 0.

Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer's disease.

Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.

Molecular docking of a series of peptidomimetics in the trypanothione binding site of T. cruzi trypanothione reductase.

Chagas' disease (CD) has been responsible for many deaths and disabilities mainly in South America. Currently, 40 million people are at risk of acquiring this disease and, existing therapies are still unsatisfactory, presenting harsh side effects. Therefore, the development of new chemical entities to reverse this state is critical.

Investigating the differential activation of vascular endothelial growth factor (VEGF) receptors.

The vascular endothelial growth factors are key mediators of angiogenesis and are also related to several physiological processes such as monocyte chemotaxis, dendritic cell development, hematopoietic stem cell survival, and many others. PlGF, VEGF, VEGFB, VEGFC and VEGFD were identified as members of the vascular endothelial growth factor family. They act by differential activation of three receptors: Flt-1, KDR and Flt-4.

The receptor-dependent QSAR paradigm: an overview of the current state of the art.

The original quantitative structure-activity relationship (QSAR) formulation was proposed by Hansch and Fujita in the 1960's and, since then QSAR analysis has evolved as a mature science, due mainly to the advances that occurred in the past two decades in the fields of molecular modeling, data analysis algorithms, chemoinformatics, and the application of graph theory in chemistry. Moreover, it is also worthy of note the exponential progress that have occurred in software and hardware development. In this context, a myriad of QSAR methods exist; from the considered "classical" approaches (known as two-dimensional (2D) QSAR), to three-dimensional (3D) and multidimensional (nD) QSAR ones.

3D-QSAR CoMFA/CoMSIA models based on theoretical active conformers of HOE/BAY-793 analogs derived from HIV-1 protease inhibitor complexes.

The three-dimensional quantitative structure-activity relationships (3D-QSAR) of a series of HOE/BAY-793 analogs (C(2)-symmetric diol peptidomimetics), developed by Budt and co-workers [Bioorg. Med. Chem.

3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors.

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.

On the structure, interactions, and dynamics of bound VEGF.

The vascular endothelial growth factor (VEGF) is believed to be the most important protein in the regulation of the angiogenic cascade. Thus, exploring the structure and dynamical properties of this growth factor and the influence of receptor and inhibitor binding to these properties may reveal new insights on VEGF's biological process and inhibition opportunities. Here we describe an analysis of molecular dynamics simulations of VEGF bound to the Flt-1 receptor, VEGF bound to the v107 peptide inhibitor, and also VEGF bound to a mutant v107.

Human Cytomegalovirus Protease: Why is the Dimer Required for Catalytic Activity?

Human cytomegalovirus (HCMV) is a pathogenic agent responsible for morbidity and mortality in immunocompromised and immunosuppressed individuals. HCMV encodes a serine protease that is essential for the production of infectious virions. In this work, we applied molecular dynamics (MD) simulations on HCMV protease models in order to investigate the experimentally observed (i) catalytic activity of the enzyme homodimer and (ii) induced-fit mechanism upon the binding of substrates and peptidyl inhibitors.

Free-energy force-field three-dimensional quantitative structure-activity relationship analysis of a set of p38-mitogen activated protein kinase inhibitors.

The p38-mitogen-activated protein kinases (p38-MAPKs) belong to a family of serine-threonine kinases activated by pro-inflammatory or stressful stimuli that are known to be involved in several diseases. Their biological importance, related to the release of inflammatory pro-cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), has generated many studies aiming at the development of selective inhibitors for the treatment of inflammatory diseases. In this work, we developed receptor-based three dimensional (3D) quantitative structure-activity relationship (QSAR) models for a series of 33 pyridinyl imidazole compounds [Liverton et al.

Construction of 4D-QSAR models for use in the design of novel p38-MAPK inhibitors.

The p38-mitogen-activated protein kinase (p38-MAPK) plays a key role in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) release during the inflammatory process, emerging as an attractive target for new anti-inflammatory agents. Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis [Hopfinger et al., J.

Interactions of 5-deazapteridine derivatives with Mycobacterium tuberculosis and with human dihydrofolate reductases.

There are major differences between the structures of human dihydrofolate reductase (hDHFR) and Mycobacterium tuberculosis dihydrofolate reductase (mtDHFR). These differences may allow us to design more selective mtDHFR inhibitors. In this paper we study the reactions of six different compounds derived from 5-deazapteridine with human and bacterial enzymes.

Theoretical evaluation of adiabatic and vertical electron affinity of some radiosensitizers in solution using FEP, ab initio and DFT methods.

The biological activity of radiosensitizers is associated to their electron affinity (EA), which can be divided in two main processes: vertical and adiabatic. In this work, we calculated the EAs of nitrofurans and nitroimidazoles (Fig. 2) using Hartree-Fock (HF) and density functional theory (DFT) methods and evaluated solvent effects (water and carbon tetrachloride) on EAs.

LIV-3D-QSAR models for PGI2 receptor ligands using multiple conformations.

A new 3D descriptor, the local intersection volume (LIV), was developed by our group and applied to the construction of 3D-QSAR models for ligands of the PGI(2) receptor (IP). The target compounds are a set of 42 aromatic heterocyclic derivatives [Meanwell et al., J.

Synthetic and theoretical studies on the reduction of electron withdrawing group conjugated olefins using the Hantzsch 1,4-dihydropyridine ester.

The Hantzsch 1,4-dihydropyridine ester (1) has been observed to be a useful selective reducing agent for the reduction of electron-withdrawing conjugated double bonds. The rate of this reaction was observed to be dependent upon the nature of the conjugated substituents and, consequently, the electronic nature of the unsaturated double bond. Theoretical calculations confirmed the importance of the HOMO-LUMO gap for this reaction and implicated a hydride transfer, agreeing with the experimentally observed reaction rate order.

Investigation of the induced-fit mechanism and catalytic activity of the human cytomegalovirus protease homodimer via molecular dynamics simulations.

Human cytomegalovirus (HCMV) is a highly species-specific DNA virus infecting up to 80% of the general population. The viral genome contains the open reading frame UL80, which encodes the full-length 80 kDa HCMV serine protease and its substrate. Full-length HCMV protease is composed of an N-terminal 256-amino-acid proteolytic domain, called assemblin, a linker region, and a C-terminal structural domain, the assembly protein precursor.