In vitro assays identified thiohydantoins with anti-trypanosomatid activity and molecular modelling studies indicated possible selective CYP51 inhibition.

This work investigates the anti-trypanosomal activities of ten thiohydantoin derivatives against the parasite Trypanosoma cruzi. Compounds with aliphatic chains (THD1, THD3, and THD5) exhibited the most promising IC against the epimastigote form of T. cruzi.

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro).

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication.

DFT calculations of copper complexes mimicking superoxide dismutase and docking studies and molecular dynamics of the transition metal complex binding to serum albumin.

Superoxide dismutase (SOD) is a metalloenzyme whose antioxidant activity is mimicked by some transition metal complexes, and such ability can be added in proteins such as the bovine serum albumin (BSA), creating a hybrid protein. In this work, density functional theory (DFT) calculations of three Cu(II)-complexes of general formula [CuLphen] (phen = phenanthroline; , L = mefenamate; , L = tolfenamate; , L = flufenamate) with SOD-like activity, and docking and molecular dynamics (MD) simulations of these complexes with the BSA were performed. The DFT calculations revealed that the complex reduction involves Cu(II) → Cu(I) reduction, the theoretical electron affinity (EA) correlated with the SOD-like activity (IC), and the contribution of the phenanthroline ligand and the metal in LUMO it's related with the complex-protein interaction (K).

Development, validation and analysis of a human profurin 3D model using comparative modeling and molecular dynamics simulations.

The emergence of new viruses can lead to the outbreak of pandemics as occurred at the end of 2019 with the coronavirus disease (or COVID-19). The fastest way to effectively control viral infections is to develop broad-spectrum antivirals that can fight at least an entire class of viruses. Profurin, the furin precursor propeptide, is responsible for the autoactivation step which is crucial for the maturation of several viral substrates.

Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on .

Leishmaniasis is a neglected tropical disease caused by species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal.

Molecular dynamics simulations of aqueous systems of inhibitor candidates for adenosine-5'-phosphosufate reductase.

Molecular dynamics (MD) simulations were used to evaluate some chelating agents as potential candidates to inhibitors for dissimilatory adenosine-5'-phosphosulfate reductase (APSrAB). Molecular docking methods were used to evaluate the best binding modes of these molecules to the enzyme at two binding sites: of the substrate (enzyme active site) by mean the redocking protocol of substrate; and of one of the [FeS] groups by mean of the clusterization protocol. The best docking poses were selected by criteria such as low energy and RMSD (redocking) and the cluster with the higher number of similar poses (clusterization), which were submitted to MD simulations.

Development of parameters compatible with the CHARMM36 force field for [FeS] clusters and molecular dynamics simulations of adenosine-5'-phosphosulfate reductase in GROMACS 2019.

DFT calculations were used to obtain parameters compatible with the CHARMM36 force field for iron-sulfur clusters (Fe-S) of the type [FeS] that are coordinated to dissimilatory adenosine-5'-phosphosulfate reductase (APSrAB). Classical molecular dynamics (MD) simulations were performed on two APSrAB systems to validate the parameters and verify the stability of the studied systems. The time analysis of the parameters inserted into the force field was in reasonable agreement with the experimental X-ray diffraction data.

Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors.

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P.

Synthesis of New Thiosemicarbazones and Semicarbazones Containing the 1,2,3-1H-triazole-isatin Scaffold: Trypanocidal, Cytotoxicity, Electrochemical Assays, and Molecular Docking.

Background: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry.

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (, , and ) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, (-). Considering the active compounds of series (-), (-), (-), and (-), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis.

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization.

Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N'-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies.

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.

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.

Molecular docking studies of marine diterpenes as inhibitors of wild-type and mutants HIV-1 reverse transcriptase.

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.

Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors.

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported.

Structural model of haptoglobin and its complex with the anticoagulant ecotin variants: structure-activity relationship study and analysis of interactions.

Recently the literature described the binding of Haptoglobin (HP) with ecotin, a fold-specific serine-proteases inhibitor with an anticoagulant profile and produced by Escherichia coli. In this work, we used some in silico and in vitro techniques to evaluate HP 3D-fold and its interaction with wild-type ecotin and two variants. Our data showed HP models conserved trypsin fold, in agreement to the in vitro immunological recognition of HP by trypsin antibodies.

Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives.

Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines.

Molecular modeling studies of the structural, electronic, and UV absorption properties of benzophenone derivatives.

Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G(d) basis set is an accurate method for optimizing the geometry of BZPs.

Hologram QSAR models of 4-[(diethylamino)methyl]-phenol inhibitors of acetyl/butyrylcholinesterase enzymes as potential anti-Alzheimer agents.

Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer's disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0.

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.

Molecular dynamics simulations of peptide inhibitors complexed with Trypanosoma cruzi trypanothione reductase.

The drugs against tropical neglected diseases, especially Chagas' Disease, were launched more than 30 years ago, and the development of resistance requires the discovery of new and more effective chemotherapeutic agents. Trypanosoma cruzi has a redox enzyme called trypanothione reductase which was successfully inhibited for peptide derivatives (McKie et al., Amino Acids, 2001, 20: 145).

CoMFA/CoMSIA 3D-QSAR of pyrimidine inhibitors of Pneumocystis carinii dihydrofolate reductase.

Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS).

Receptor-dependent 4D-QSAR analysis of peptidemimetic inhibitors of Trypanosoma cruzi trypanothione reductase with receptor-based alignment.

Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells.