Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their ...antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10 μg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1’s putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1 μM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1‐compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.
A series of spiro‐acridine derivatives have been identified with activity against Leishmania chagasi. However, their mechanism of action has not been elucidated. In this work, we used the computational target fishing method to identify the target and we identified the enzyme Pteridine reductase 1. The predicted target is supported by in vitro assays that confirm the conformation of the complex.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show ...that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.
The concept of "one target, one drug, one disease" is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine ...derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC
of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Quantitative Structure-Activity Relationship (QSAR) is a computer-aided technology in the field of medicinal chemistry that seeks to clarify the relationships between molecular structures and their ...biological activities. Such technologies allow for the acceleration of the development of new compounds by reducing the costs of drug design. This work presents 3D-QSARpy, a flexible, user-friendly and robust tool, freely available without registration, to support the generation of QSAR 3D models in an automated way. The user only needs to provide aligned molecular structures and the respective dependent variable. The current version was developed using Python with packages such as scikit-learn and includes various techniques of machine learning for regression. The diverse techniques employed by the tool is a differential compared to known methodologies, such as CoMFA and CoMSIA, because it expands the search space of possible solutions, and in this way increases the chances of obtaining relevant models. Additionally, approaches for select variables (dimension reduction) were implemented in the tool. To evaluate its potentials, experiments were carried out to compare results obtained from the proposed 3D-QSARpy tool with the results from already published works. The results demonstrated that 3D-QSARpy is extremely useful in the field due to its expressive results.
Sexually Transmitted Diseases (STDs) refer to a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity. Among STDs widely ...reported in the literature, viral sexual diseases have been increasing in a number of cases globally. This emphasizes the need for prevention and treatment. Among the methods widely used in drug planning are Computer-Aided Drug Design (CADD) studies and molecular docking which have the objective of investigating molecular interactions between two molecules to better understand the three -dimensional structural characteristics of the compounds. This review will discuss molecular docking studies applied to viral STDs, such as Ebola virus, Herpes virus and HIV, and reveal promising new drug candidates with high levels of specificity to their respective targets.
The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the ...advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases.
Lipopeptides are biosurfactants, substances with a high surfactant potential where each family corresponds to a group of isoforms that differs in the peptide's composition and the length of the lipid ...chain. Among them, iturin and surfactin, lipopeptides with high surfactant and antibiotic potential, stand out. As a lipopeptide, they are a set of isoforms, biosynthesized or engineered, where the relationship between their structures and properties helps choose and direct the product to the final application. Those applications can range from the surface cleaning and disinfection industry to crude oil recovery, in addition to being the subject of studies in medical and pharmacological processes. In the context of COVID-19, the present study aims to produce an extract of lipopeptides rich in surfactin and iturin's isoforms through the cultivation of Bacillus subtilis UFPEDA 438, using sugarcane molasses as a substrate, as well as to evaluate their biological activity in vitro, including their antiviral potential through in silico analysis, against the 4 main target proteins of SARS-CoV 2. The results showed maximum productivity of 148.55 ± 4.67 mg/L of surfactin with satisfactory levels of emulsification activities, a reduction in the surface tension of water by up to 55.24%, and strong antioxidant activities. Regarding the in silico evaluation, the greatest interaction of the studied biosurfactants was with the Spyke protein, which is crucial for the binding of the virus with the host human cell. The achieved results point to the extract produced as a promising constituent in the elaboration of products with high antioxidant and surfactant potential; and, in addition, moves future trials of his antiviral activity against SARS-CoV-2.
•Surfactin and iturin were produced by Bacillus subtilis UFPEDA 438 using sugarcane molasses as a substrate.•Biological activity in vitro and in silico were assayed against the 4 main target proteins of SARS-CoV 2.•Maximum productivity of 148.55 ± 4.67 mg/L of surfactin with reduction in the surface tension of water by up to 55.24%.•Insilico evaluation showed a great interaction of the studied biosurfactants with the Spyke protein from SARS-CoV 2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
9.
Multi-Target Drugs Against Metabolic Disorders Scotti, Luciana; Monteiro, Alex France Messias; de Oliveira Viana, Jéssika ...
Endocrine, metabolic & immune disorders drug targets,
01/2019, Volume:
19, Issue:
4
Journal Article
Peer reviewed
Metabolic disorders are a major cause of illness and death worldwide. Metabolism is the process by which the body makes energy from proteins, carbohydrates, and fats; chemically breaking these down ...in the digestive system towards sugars and acids which constitute the human body's fuel for immediate use, or to store in body tissues, such as the liver, muscles, and body fat.
The efficiency of treatments for multifactor diseases has not been proved. It is accepted that to manage multifactor diseases, simultaneous modulation of multiple targets is required leading to the development of new strategies for discovery and development of drugs against metabolic disorders.
In silico studies are increasingly being applied by researchers due to reductions in time and costs for new prototype synthesis; obtaining substances that present better therapeutic profiles.
In the present work, in addition to discussing multi-target drug discovery and the contributions of in silico studies to rational bioactive planning against metabolic disorders such as diabetes and obesity, we review various in silico study contributions to the fight against human metabolic pathologies.
In this review, we have presented various studies involved in the treatment of metabolic disorders; attempting to obtain hybrid molecules with pharmacological activity against various targets and expanding biological activity by using different mechanisms of action to treat a single pathology.
Neglected Tropical Diseases (NTDs) form a group of diseases that are strongly associated with poverty, flourish in impoverished environments, and thrive best in tropical areas, where they tend to ...present overlap. They comprise several diseases, and the symptoms vary dramatically from disease to disease, often causing from extreme pain, and untold misery that anchors populations to poverty, permanent disability, and death. They affect more than 1 billion people worldwide; mostly in poor populations living in tropical and subtropical climates. In this review, several complementary in silico approaches are presented; including identification of new therapeutic targets, novel mechanisms of activity, high-throughput screening of small-molecule libraries, as well as in silico quantitative structure-activity relationship and recent molecular docking studies. Current and active research against Sleeping Sickness, American trypanosomiasis, Leishmaniasis and Schistosomiasis infections will hopefully lead to safer, more effective, less costly and more widely available treatments against these parasitic forms of Neglected Tropical Diseases (NTDs) in the near future.
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