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Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).

Cholinesterases are a family of enzymes that catalyze the hydrolysis of neurotransmitter acetylcholine. There are two types of cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which differ in their distribution in the body. Currently, cholinesterase inhibitors (ChEI) represent the treatment of choice for Alzheimer's disease (AD). In this paper, we report the synthesis and inhibitory effect on both enzymes of four new peptides structurally related to P1-Hp-1971 (amphibian skin peptide found in our previous work. Sequence: TKPTLLGLPLGAGPAAGPGKR-NH2). The bioassay data and cytotoxicity test show that some of the compounds possess a significant AChE and BChE inhibition and no toxic effect. The present work demonstrates that diminution of the size of the original peptide could potentially result in new compounds with significant cholinesterase inhibition activity, although it appears that there is an optimal size for the sequence. We also conducted an exhaustive molecular modeling study to better understand the mechanism of action of these compounds by combining docking techniques with molecular dynamics simulations on BChE. This is the first report about amphibian peptides and the second one of natural peptides with ChE inhibitory activity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

In this work, Halogen Bond (X-bond) interactions formed by halogenated ligands (LX) at the Dopamine Receptor D2 (DRD2) binding pocket were studied by Molecular Dynamics (MD) and charge density analysis. The X-bonds were contrasted with the Hydrogen Bond (H-bond) interactions established by hydroxylated analogs (LOH, where X was replaced by OH). The ligands for this study were extracted from a dataset of compounds deposited in ZINC database that were active in binding assays to DRD2. This dataset was subjected to the filtering rules by employing cheminformatics tools to find the LX/LOH pairs that were then submitted to MD simulations. A homology model of DRD2 was employed for the simulations because no crystal structure is yet available for the receptor. To mimic the positive cap (σ-hole) on the halogen atom, a massless, positive charged extra-point was introduced in the force field. An analysis of the charge density (QTAIM) was performed on reduced models of simulated complexes to explain their binding differences. Results show that the halogen atom tends to form X-bond with protein backbone oxygen atom. Two out of the four halogenated ligands studied form a specific X-bond with the carbonyl oxygen of Ser193. This specific X-bond decreases the inherent propensity of transmembrane 5 to unfolding. These results suggest a possible role of the X-bond as a protein secondary structure modulator because of the ability of the halogen to interact with the protein backbone. Copyright © 2016 John Wiley & Sons, Ltd.

The synthesis, in vitro evaluation and conformational study of several small-size peptides acting as antibacterial agents are reported. Among the compounds evaluated, the peptides Arg-Gln-Ile-Lys-Ile-Trp-Arg-Arg-Met-Lys-Trp-Lys-Lys-NH2 , Arg-Gln-Ile-Lys-Ile-Arg-Arg-Met-Lys-Trp-Arg-NH2 , and Arg-Gln-Ile-Trp-Trp-Trp-Trp-Gln-Arg-NH2 exhibited significant antibacterial activity. These were found to be very active antibacterial compounds, considering their small molecular size. In order to better understand the antibacterial activity obtained for these peptides, an exhaustive conformational analysis was performed, using both theoretical calculations and experimental measurements. Molecular dynamics simulations using two different media (water and trifluoroethanol/water) were employed. The results of these theoretical calculations were corroborated by experimental circular dichroism measurements. A brief discussion on the possible mechanism of action of these peptides at molecular level is also presented. Some of the peptides reported here constitute very interesting structures to be used as starting compounds for the design of new small-size peptides possessing antibacterial activity.

New nitrosopyrimidines were synthesized and evaluated as potential antibacterial agents. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines displayed significant antibacterial activity against human pathogenic bacteria. Among them compounds 1c, 2a–c, and 9a–c exhibited remarkable activity against methicillin-sensitive and -resistant Staphylococcus aureus, Escherichia coli, Yersinia enterocolitica, and Salmonella enteritidis. A detailed structure–activity relationship study, supported by theoretical calculations, aided us to identify and understand the minimal structural requirements for the antibacterial action of the nitrosopyrimidines reported here. Thus, our results have led us to identify a topographical template that provides a guide for the design of new nitrosopyrimidines with antibacterial effects.

In this paper, we reported the results obtained by charge density analysis of the network of non-covalent interactions (NCI) established in the binding pocket of a receptor, in relevant conformations of ligand – receptor complexes. Starting with strong and moderate hydrogen bonds, moving on to weaker polar interactions and ending with stacking and T-shape like interactions between aromatic rings, all of them have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules. Also, natural bond orbital analysis was carried out, in order to evaluate quantitatively the electronic population of the aromatic rings. The analysis of our “case study” shows that the interactions of the catechol OH groups of the ligand, in the different conformations of the dopamine (DA) – D2 receptor complex, determine the decrease or increase of the electron density on the aromatic ring of DA. In turn, the electronic population of the aromatic ring of DA defines its orientation within the binding site and the type of interactions that it establishes with the aromatic rings of the receptor. Although the approach used here was traditionally applied to the study of NCI in small molecules complexes in gas phase, we show through this work that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event. Copyright © 2013 John Wiley & Sons, Ltd.

An ab initio and Density Functional Theory (DFT) study of the conformational properties of cyclododecane was carried out. The energetically preferred equilibrium structures, their relative stability, and some of the transition state (TS) structures involved in the conformational interconversion pathways were analyzed from RHF/6-31G(d), B3LYP/6-31G(d,p) and B3LYP/6311++G(d,p) calculations. Aug-cc-pVDZ//B3LYP/6311++G(d,p) single point calculations predict that the multistep conformational interconversion mechanism requires 11.07 kcal/mol, which is in agreement with the available experimental data. These results allow us to form a concise idea about the internal intricacies of the preferred forms of cyclododecane, describing the conformations as well as the conformational interconversion processes in the conformational potential energy hypersurface. Our results indicated that performing an exhaustive analysis of the potential energy curves connecting the most representative conformations is a valid alternate tool to determine the principal conformational interconversion paths for cyclododecane. This methodology represents a satisfactory first approximation for the conformational analysis of medium- and large-size flexible cyclic compounds. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012

In this study, we described quantitatively the interactions between two new amino-2H-imidazole inhibitors ((R)-1t and (S)-1m) and BACE1 using a hybrid quantum mechanics-molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The combined QM/MM-QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range. Fil: Vega Hissi, Esteban Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina Fil: Tosso, Rodrigo David. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia. Departamento de Quimica; Argentina Fil: Gutierrez, Lucas Joel. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

A conformational and electronic study on N-phenylalkyl-3,4-dichloromaleimides, a new series of antifungal compounds, was carried out. In this study ab initio [RHF/3-21G and RHF/6-31G(d)] and density functional theory (B3LYP/6-31G(d)) calculations were performed. The effect of solvent (water) was taken into account by performing calculations with the isodensity polarizable continuum model method. The electronic study of the compounds was carried out using molecular electrostatic potentials. The presence of two symmetrical aromatic systems reduces notably the conformational possibilities of these maleimides. The results permit the recognition of the minimal structural requirements for the production of the antifungal response; a 3,4-dichloroimido ring and a benzene ring appear to be indispensable. Also, theoretical calculations suggest that the optimum interatomic distance between these moieties is about 3.5–5.0 A. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003