Spiro-Acridine Compound as a Pteridine Reductase 1 Inhibitor: in silico Target Fishing and in†vitro Studies.

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.

The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors.

A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.

Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies.

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 IC50 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.

Computer-Aided Drug Design for the Identification of Novel Antischistosomal Compounds.

Schistosomiasis is a chronic neglected tropical disease, highlighted by the presence of Schistosoma worms, which presents in advanced cases in approximately 80 countries, affecting almost 300 million people. The treatment is based on only one drug, praziquantel, a drug discovered in the 1970s that shows moderate efficacy against the adult parasite, but low efficacy against the larval stages of the parasite. Therefore, the use of only one drug has brought concerns and losses on drug-resistance cases, necessitating the development of new effective chemotherapeutic agents against Schistosoma species. One of the strategies that have been implemented in drug development is the computer-aided drug design (CADD), investigating the structural characteristics of the compounds and targets in order to understand their actions and biological activities through 3D virtual manipulation, as the QSAR applied to ligands and molecular docking applied to a respective biological target. These studies help to extract information and characteristics relevant to the activity, as well as to predict potential applications and activity. Therefore, this chapter will present the main validated biological targets of the genus Schistosoma, as thioredoxin glutathione reductase (TGR), histone deacetylases (HDAC 1, HDAC 8), dihydroorotate dehydrogenase, sirtuin protein and cathepsin L1, as well as reports of CADD in literature applied to the development of drugs against schistosomiasis, providing compounds with high pharmacological potential and high specificity.

Recent Theoretical Studies Concerning Important Tropical Infections.

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.

The Azoles in Pharmacochemistry: Perspectives on the Synthesis of New Compounds and Chemoinformatic Contributions.

Due to their versatile biological activity, Azoles are widely studied in pharmacochemistry. It is possible to use them in many applications and in studies aimed at discovering antiparasitic, antineoplastic, antiviral, antimicrobial compounds; and in the production of materials for treatment of varied pathologies. Based on their biological activity, our review presents several studies that involve this class of organic compounds. A bibliographic survey of this type can effectively contribute to pharmaceutical sciences, stimulating the discovery of new compounds, and structural improvements to biological profiles of interest. In this review, articles are discussed involving the synthesis of new compounds and chemoinformatic contributions. Current applications of azoles in both the pharmaceutical and agri-business sectors are well known, yet as this research highlights, azole compounds can also bring important contributions to the fight against many diseases. Among the heterocyclics, azoles are increasingly studied by research groups around the world for application against tuberculosis, HIV, fungal and bacterial infections; and against parasites such as leishmaniasis and trypanosomiasis. Our hope is that this work will help arouse the interest of research groups planning to develop new bioactives to fight against these and other diseases.

In Silico Studies against Viral Sexually Transmitted Diseases.

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.

Multi-Target Drugs Against Metabolic Disorders.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. DISCUSSION: 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. CONCLUSION: 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.

Dengue Virus Inhibition Targets: A Review and Docking Study.

Dengue like any neglected tropical disease affects a large part of the world population. In this disease, the infection is caused by arboviruses transmitted by the A. aegypti and A. albopictus mosquito, in which its most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic of such as fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In the studies shown, in silico tests were performed as molecular docking, functional density analysis, molecular orbitals energies with the analyses of the interactions between bioactives and the targets studied. However, in addition to discussing the fight against dengue virus infection through different routes, in this paper, some in silico results of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism.

Multi-Target Antitubercular Drugs.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which has high levels of mortality worldwide and has already gained resistance to first- and second-line drugs. The study by new chemical entities with promising activities becomes paramount to broaden the therapeutic strategies in the cure of the patients affected with this disease. In this context, in this review we report the discovery of 3 classes of compounds that can simultaneously interact with more than one target of Mycobacterium tuberculosis.

Hybrid Compounds as Direct Multitarget Ligands: A Review.

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.