Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13–15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13–15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.We acknowledge the support provided by the PROPESP/UFPA and CNPq for financial suppor

Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2

settingsOrder Article Reprints Open AccessArticle Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2 by Ruan S. Bastos 1,2,*,Lúcio R. de Lima 1,2,Moysés F. A. Neto 3,Maryam 4,Numan Yousaf 4ORCID,Jorddy N. Cruz 2ORCID,Joaquín M. Campos 5,6ORCID,Njogu M. Kimani 7ORCID,Ryan S. Ramos 2ORCID andCleydson B. R. Santos 1,2,*ORCID 1 Graduate Program in Medicinal Chemistry and Molecular Modeling, Federal University of Pará, Belem 66075-110, PA, Brazil 2 Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapa 68903-419, AP, Brazil 3 Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil 4 Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad 45550, Pakistan 5 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain 6 Biosanitary Institute of Granada (ibs.GRANADA), University of Granada, 18071 Granada, Spain 7 Department of Physical Sciences, University of Embu, Embu 6-60100, Kenya * Authors to whom correspondence should be addressed. Int. J. Mol. Sci. 2023, 24(10), 8814; https://doi.org/10.3390/ijms24108814 Received: 12 September 2022 / Revised: 23 November 2022 / Accepted: 28 November 2022 / Published: 16 May 2023 (This article belongs to the Special Issue The Research about Computer-Aided Drug Design) Download Browse Figures Versions Notes Abstract When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts’ angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein’s crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport®. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of −8.645 kcal·mol−1, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC50 values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.Pró-reitoria de Pesquisa e Pós-graduação (PROPESP) from Federal University of Pará (UFPA)

Alkylated Sesamol Derivatives as Potent Antioxidants

Sesamol is a phenolic derivative. Its antioxidant activity is low than that of Trolox and depends on benzodioxole moiety. Thus, a molecular modification strategy through alkylation, inspired by natural and synthetic antioxidants, was studied by molecular modeling at the DFT/B3LYP level of theory by comparing the 6-31+G(d,p) and 6-311++G(2d,2p) basis sets. All proposed derivatives were compared to classical related antioxidants such as Trolox, t-butylated hydroxytoluene (BHT) and t-butylated hydroxyanisole (BHA). According to our results, molecular orbitals, single electron or hydrogen-atom transfers, spin density distributions, and alkyl substitutions at the ortho positions related to phenol moiety were found to be more effective than any other positions. The trimethylated derivative was more potent than Trolox. t-Butylated derivatives were stronger than all other alkylated derivatives and may be new alternative forms of modified antioxidants from natural products with applications in the chemical, pharmaceutical, and food industries.PROPESP/UFPANational Council for Scientific and Technological Development (CNPq

Scientific communication: Art o Technique?

El último fin del científico es comunicar la información de la forma más comprensible y rápida y se necesitan algunas pautas para cumplir este objetivo. Este artículo intenta orientar y responder a cuestiones que pueden surgir a los autores que desean escribir artículos o exponer una comunicación oral, ahorrarles tiempo y asegurarles claridad y coherencia. La exposición oral es una responsabilidad pero, también, es una oportunidad única que puede proporcionar grandes satisfacciones, después de seguir un mínimo de reglas básicas.The ultimate aim of a scientist is to communicate information in the most understandable and expedient fashion, and to accomplish this goal several guidelines are needed. This paper is intended to guide and answer questions for authors who wish to write papers or to deliver oral presentations, to save them time, and to ensure clarity and consistency. Giving oral presentations is a responsibility, but it is also an unique opportunity that can bring great satisfaction, after following a minimun of a few basic rules

Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, which have shown significant growth. The main control strategy is the elimination of the vector, carried out through various education programs, to change human habits, but the most usual is biological control, together with environmental management and chemical control. The most commonly insecticide used is temephos (an organophosphorus compound), but Aedes aegypti populations have shown resistance and the product is highly toxic, so we chose it as a template molecule to perform a ligand-based virtual screening in the ChemBrigde (DIVERSet-CL subcollection) database, searching for derivatives with similarity in shape (ROCS) and electrostatic potential (EON). Thus, fourty-five molecules were filtered based on their pharmacokinetic and toxicological properties and 11 molecules were selected by a molecular docking study, including binding affinity and mode of interaction. The L46, L66 and L68 molecules show potential inhibitory activity for both the insect (-9.28, -10.08 and -6.78 kcal/mol, respectively) and human (-6.05, 6.25 and 7.2 kcal/mol respectively) enzymes, as well as the juvenile hormone protein (-9.2; -10.96 and -8.16 kcal/mol, respectively), showing a significant difference in comparison to the template molecule temephos. Molecules L46, L66 and L68 interacted with important amino acids at each catalytic site of the enzyme reported in the literature. Thus, the molecules here investigated are potential inhibitors for both the acetylcholinesterase enzymes and juvenile hormone protein–from insect and humans, characterizing them as a potential insecticide against the Aedes aegypti mosquito

Hierarchical Virtual Screening and Binding Free Energy Prediction of Potential Modulators of Aedes Aegypti Odorant-Binding Protein 1

The Aedes aegypti mosquito is the main hematophagous vector responsible for arbovirus transmission in Brazil. The disruption of A. aegypti hematophagy remains one of the most efficient and least toxic methods against these diseases and, therefore, efforts in the research of new chemical entities with repellent activity have advanced due to the elucidation of the functionality of the olfactory receptors and the behavior of mosquitoes. With the growing interest of the pharmaceutical and cosmetic industries in the development of chemical entities with repellent activity, computational studies (e.g., virtual screening and molecular modeling) are a way to prioritize potential modulators with stereoelectronic characteristics (e.g., pharmacophore models) and binding affinity to the AaegOBP1 binding site (e.g., molecular docking) at a lower computational cost. Thus, pharmacophore- and docking-based virtual screening was employed to prioritize compounds from Sigma-Aldrich (R) (n = 126,851) and biogenic databases (n = 8766). In addition, molecular dynamics (MD) was performed to prioritize the most potential potent compounds compared to DEET according to free binding energy calculations. Two compounds showed adequate stereoelectronic requirements (QFIT > 81.53), AaegOBP1 binding site score (Score > 42.0), volatility and non-toxic properties and better binding free energy value (Delta G < -24.13 kcal/mol) compared to DEET ((N,N-diethyl-meta-toluamide)) (Delta G = -24.13 kcal/mol)

Hierarchical Virtual Screening of Potential New Antibiotics from Polyoxygenated Dibenzofurans against Staphylococcus aureus Strains

Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ph16101430/s1, Table S1. Spatial Coordinates of the Pharmacophoric Model.Staphylococcus aureus is a microorganism with high morbidity and mortality due to antibiotic-resistant strains, making the search for new therapeutic options urgent. In this context, computational drug design can facilitate the drug discovery process, optimizing time and resources. In this work, computational methods involving ligand- and structure-based virtual screening were employed to identify potential antibacterial agents against the S. aureus MRSA and VRSA strains. To achieve this goal, tetrahydroxybenzofuran, a promising antibacterial agent according to in vitro tests described in the literature, was adopted as the pivotal molecule and derivative molecules were considered to generate a pharmacophore model, which was used to perform virtual screening on the Pharmit platform. Through this result, twenty-four molecules were selected from the MolPort® database. Using the Tanimoto Index on the BindingDB web server, it was possible to select eighteen molecules with greater structural similarity in relation to commercial antibiotics (methicillin and oxacillin). Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the eighteen most similar molecules, showed that only three exhibited desired properties (LB255, LB320 and LB415). In the molecular docking study, the promising molecules LB255, LB320 and LB415 showed significant values in both molecular targets. LB320 presented better binding affinity to MRSA (−8.18 kcal/mol) and VRSA (−8.01 kcal/mol) targets. Through PASS web server, the three molecules, specially LB320, showed potential for antibacterial activity. Synthetic accessibility (SA) analysis performed on AMBIT and SwissADME web servers showed that LB255 and LB415 can be considered difficult to synthesize and LB320 is considered easy. In conclusion, the results suggest that these ligands, particularly LB320, may bind strongly to the studied targets and may have appropriate ADME/Tox properties in experimental studies

In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

This research was funded by CSIC, grant number PIE202020E041; and in part by the NIFA through the Agricultural Research Program at North Carolina Agricultural and Technical State University (Evans-Allen Program, project number NC.X-291-5-15-170-1).Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed.CSIC, grant number PIE202020E041NIFA through the Agricultural Research Program at North Carolina Agricultural and Technical State University (Evans-Allen Program, project number NC.X-291-5-15-170-1

You must be the change you want to see in the University

Se discutirán las dos primeras misiones de la Universidad, tales como la docencia y la investigación. Además, las relaciones inter-personales son fundamentales en todo grupo humano y se abordará el papel del liderazgo en el grupo de investigación de acuerdo con las modernas tendencias del mundo empresarial. La Universidad española se encuentra en una situación excesivamente alejada de la realidad social y económica en la que vivimos. El enfoque del Espacio Europeo de Enseñanza Superior puede subsanar estas deficiencias, pero la adaptación conlleva, en mayor o menor grado, una transformación del modelo educativo actual. Lo que no está claro es que las universidades españolas hayan alcanzado o estén en vías de alcanzar plenamente la nueva configuración de la Declaración de Bolonia. Más bien están en una situación transitoria, ambigua, en la que permanecen rasgos anteriores con los nuevos. Con respecto al papel carismático del líder dentro de un grupo, merecen ser destacados aspectos tales como la motivación, delegación y resolución de conflictos, entre los muchos valores que deben adornarlo. La Universidad de Granada es una institución muy grande. El secreto para que funcione esta macro estructura es que cada uno de sus componentes, dentro de su status, se identifique con sus principios y se comprometa a cumplir con sus funciones, tanto particulares como generales. El secreto del éxito es la ilusión, trabajo y generosidad. Es así y sólo así, cuando el trabajo y la colaboración comprometida de todos sus miembros, dará lugar a una Universidad mejor.Teaching and research, two missions of the University, will be discussed herein. Moreover, the interpersonal relationships are fundamental in all human groups and the role of the leadership in the research group will be tackled according to the modern tendencies of the business world. The Spanish University has been too distanced from the social and economical reality. The approach of the European higher education system may overcome all these shortcomings, but the adaptation may lead, to a greater or a lesser degree, to a transformation of the present education system. It is not clear that the Spanish universities have reached or are now being fully reaching the new configuration of the Bologna Declaration. They are rather in a temporary ambiguous situation, in which some previous features remain with the new ones. In relation to the charismatic role of the leader within a group, aspects such as motivation, delegation of functions and resolution of conflicts warrant the greatest attention among the many values that must enhance it. The University of Granada is a vast institution. The secret for this macro-structure to work is that its components, each within its own status, be identified with its principles and be committed to observing its functions, both particular and general. The secret of the success is illusion, work and generosity. Only thus, when work and collaboration implicating all its members is a better University possible