scholarly journals Molecular Modeling and Chemical Synthesis of New Safrol Oxime Ether Derivatives

2021 ◽  
Author(s):  
Mariana Silva ◽  
Marcia Veloso ◽  
Thaynan Chagas ◽  
Mirian Cordeiro ◽  
Levy Alves ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Molecular Targets ◽  
New Drugs ◽  
Public Health Issue ◽  
Neglected Tropical Disease ◽  
Cyclin Dependent Kinase ◽  
Covalent Bonds ◽  
High Affinity ◽  
High Degree ◽  
Affinity Profile

Leishmaniasis, a neglected tropical disease with a high worldwide incidence, is considered a public health issue in Minas Gerais and Brazil, with a high degree of morbidity, not to mention the lack of therapeutic arsenal. The cysteine protease (rCPB2.8) and cyclin dependent kinase (CRK3), important enzymes for the parasite’s feasibility, were the targets chosen for investigation of the new drugs. The following study aimed to analyze several oximic derivatives starting from safrol, which can present an affinity profile for selected molecular targets using tools from molecular modeling and bioinformatics, planning and synthesis of brand new substances being tested for leishmanicidal drugs. The study allowed to verify that three oximic derivatives (5a, 5f and 5h) presented high affinity for the CRK3 enzyme, and that the compounds 5c and 5g presented good interaction by the amino acids of the catalytic site of the rCPB2.8 enzyme with atomic distances capable of generating covalent bonds, which are essential for enzyme inhibitory activity.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

scholarly journals Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1778
Author(s):  
Pakhuri Mehta ◽  
Przemysław Miszta ◽  
Sławomir Filipek
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Modeling ◽  
Molecular Targets ◽  
Histamine Receptors ◽  
Experimental Characterization ◽  
Complex Disorders ◽  
Theoretical Investigations ◽  
Recent Developments

The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer’s disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014–2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors.

Molecular Modeling Studies Focused on 5-HT7versus 5-HT1ASelectivity. Discovery of Novel Phenylpyrrole Derivatives with High Affinity for 5-HT7Receptors

2005 ◽  
Vol 45 (4) ◽  
pp. 1075-1081 ◽  
Author(s):  
Alban Lepailleur ◽  
Ronan Bureau ◽  
Magalie Paillet-Loilier ◽  
Frédéric Fabis ◽  
Nicolas Saettel ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
High Affinity ◽  
Modeling Studies ◽  
Molecular Modeling Studies

scholarly journals Trypanosoma cruzi Presenilin-Like Transmembrane Aspartyl Protease: Characterization and Cellular Localization

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1564
Author(s):  
Guilherme C. Lechuga ◽  
Paloma Napoleão-Pêgo ◽  
Carolina C. G. Bottino ◽  
Rosa T. Pinho ◽  
David W. Provance-Jr ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cellular Localization ◽  
Secretory Pathway ◽  
Chronic Phase ◽  
Basic Research ◽  
New Drugs ◽  
Public Health Issue ◽  
Spot Synthesis ◽  
Major Public Health Issue ◽  
Computational Analyses

The increasing detection of infections of Trypanosoma cruzi, the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in T. cruzi to identify new targets. Here, we report on the T. cruzi presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with T. vivax separate from protozoans. Computational analyses suggest it contains nine transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT-synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles, and endoplasmic reticulum in parasites by whole-cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a target for the generation of new therapeutics specific to the T. cruzi.

scholarly journals Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 983 ◽  
Author(s):  
Diana Morales-Jadán ◽  
José Blanco-Salas ◽  
Trinidad Ruiz-Téllez ◽  
Francisco Centeno
Keyword(s):  
Free Energy ◽  
Active Site ◽  
In Silico ◽  
Binding Free Energy ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Physiological Importance ◽  
Promising Tool ◽  
Binding Pockets ◽  
Simulation Results

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.

scholarly journals Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Elaine F. F. da Cunha ◽  
José E. Resende ◽  
Tanos C. C. Franca ◽  
Mateus Aquino Gonçalves ◽  
Felipe R. de Souza ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Neurodegenerative Disorders ◽  
Acetylcholinesterase Inhibitors ◽  
Molecular Target ◽  
New Drugs ◽  
Ache Inhibitors ◽  
Progressive Loss ◽  
Molecular Modeling Studies ◽  
Dynamics Simulations

Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson’s, Alzheimer’s, and Huntington’s, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE inhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional molecular dynamics simulations steps.

New Potential Molecular Targets for Cannabis Addition

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
M. Vieira-Coelho ◽  
J. Azevedo ◽  
M. Esteves
Keyword(s):  
Nicotinic Receptors ◽  
Molecular Targets ◽  
New Drugs ◽  
Laboratory Animals ◽  
Drug Reinforcement ◽  
Cannabis Dependence ◽  
Adverse Health Effects ◽  
Treatment Of Obesity ◽  
Oral Doses ◽  
Orally Active

Cannabis is considerer the most widely abused illicit drug in the world. The recent rising prevalence of cannabis use by young adults and increasing evidence of adverse health effects makes the search for new pharmacotherapy to reduce cannabis abuse extremely important. To date no medication has been approved for the treatment of cannabis addition.This study reviews recent results with potential interest for future pharmacological treatment of Cannabis dependence. Most of the relevant data obtained for treatment of cannabis dependence target the endocannabinoid or the central cholinergic systems, both involved and interact in brain systems implicated drug reinforcement. In laboratory animals blockade of cannabinoids CB1 receptors reverses central effects of cannabinoids. Rimonabant is a selective, orally active, cannabinoid CB1 receptor antagonist (inverse agonist) that has been shown in animals to modulate cannabinoid signaling in brain reward circuit. In humans, it has been shown that rimonabant, single or repeated oral doses blocked psychological and physiological effects of smoked marijuana (1). Although psychiatric adverse side affects like depression were reported with rimonabant, this compound was already been approved for treatment of obesity and metabolic syndrome. Very recently, blockade of α7 nicotinic receptors was shown to reverse abuse-related behavioral and neurochemical effects of cannabinoids in rats (2).In conclusion, besides cannabinoid CB1 receptor, the homomeric α7 nicotinic receptors are novel molecular targets in the development of new drugs for treatment of cannabis addition.

New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer’s disease: Synthesis, molecular modeling, NMR, and biological evaluation

2017 ◽  
Vol 36 (15) ◽  
pp. 4099-4113 ◽  
Author(s):  
Denise Cristian Ferreira Neto ◽  
Josélia Alencar Lima ◽  
Joyce Sobreiro Francisco Diz de Almeida ◽  
Tanos Celmar Costa França ◽  
Claudia Jorge do Nascimento ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Biological Evaluation ◽  
New Drugs

scholarly journals Affibody Molecules as Targeting Vectors for PET Imaging

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 651 ◽  
Author(s):  
Vladimir Tolmachev ◽  
Anna Orlova
Keyword(s):  
Molecular Targets ◽  
Scaffold Proteins ◽  
Preclinical Studies ◽  
Her2 Expression ◽  
Affibody Molecules ◽  
Breast Cancer Metastases ◽  
High Affinity ◽  
Factors Influencing ◽  
Cancer Metastases ◽  
Positron Emitters

Affibody molecules are small (58 amino acids) engineered scaffold proteins that can be selected to bind to a large variety of proteins with a high affinity. Their small size and high affinity make them attractive as targeting vectors for molecular imaging. High-affinity affibody binders have been selected for several cancer-associated molecular targets. Preclinical studies have shown that radiolabeled affibody molecules can provide highly specific and sensitive imaging on the day of injection; however, for a few targets, imaging on the next day further increased the imaging sensitivity. A phase I/II clinical trial showed that 68Ga-labeled affibody molecules permit an accurate and specific measurement of HER2 expression in breast cancer metastases. This paper provides an overview of the factors influencing the biodistribution and targeting properties of affibody molecules and the chemistry of their labeling using positron emitters.

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