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In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 µg/mL and 16-64 µg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 µg/mL and 16 µg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10-52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition. Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which ß-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.
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Antituberculosos , Indolizinas , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Antituberculosos/farmacología , Antituberculosos/química , Indolizinas/química , Indolizinas/farmacología , Simulación de Dinámica Molecular , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/metabolismo , Relación Estructura-ActividadRESUMEN
According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation.Communicated by Ramaswamy H. Sarma.
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Cancer is still a major cause of death worldwide. Unfortunately, the majority of current anticancer treatments suffer many limitations, mainly emergence of resistance and lack of selectivity which necessitate the search for new therapeutics. The TOPK enzyme emerges as a promising target due to its overexpression in many cancer types while being rarely detected in normal tissues. Therefore, targeting TOPK would affect the malignant activity of cancerous cells while sparing normal ones. Further, its vital role in cell division, particularly in cytokinesis, adds to its safety to normal non-multiplying cells. In this study, a combined ligand and structure-based approach was utilized to identify potential TOPK inhibitors. Previously, we identified TOPK inhibitors using a structure-based approach following the construction of a 3D homology model of the TOPK enzyme. Herein, the most active identified inhibitor (lead) was used as a search query to conduct similarity search against PubChem and ChemBridge databases. Retrieved hits were filtered using drug-like filters, docked into the ATP binding site of the enzyme, and finally, the binding free energies of all docked poses were calculated. Based on the computational scores, eight hits were selected as potential TOPK inhibitors. The predicted ADMET descriptors of the eight selected hits were generally favorable. Further, MD simulations of the top scoring hit were conducted to investigate its binding dynamics compared to the lead compound and OTS964 which agreed with the docking results and propose the selected hits as potential TOPK inhibitors. Yet, biochemical testing is still needed to validate these results.Communicated by Ramaswamy H. Sarma.
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Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.
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Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.
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Antineoplásicos , Productos Biológicos , Neoplasias , Adenosina Difosfato , Alcaloides , Antineoplásicos/química , Antineoplásicos/farmacología , Caspasas , Femenino , Humanos , Isoquinolinas , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismo , RibosaRESUMEN
Cyclodextrin-based nanosponges are widely investigated for several applications and are considered potential drug carriers. The method of nanosponges preparation involves the use of chemical cross-linking agents where the properties of Nanosponges can be affected. This study compared the resulting differences in the final nanosponges' properties using carbonate and dianhydride crosslinkers. Diphenyl carbonate and EDTA dianhydride were used for the synthesis of nanosponges. Both types of nanosponges were loaded with curcumin as a model drug. Physicochemical characterizations, including PXRD, DSC, FTIR, scanning electron microscopy, AFM, particle size, zeta potential, and surface area analysis, were carried out for the prepared nanosponges. Curcumin release and drug content were also evaluated. Nanosponges prepared by Diphenyl carbonate crosslinker resulted in an amorphous form compared to crystalline EDTA-nanosponges. This study reported the successful inclusion and complexation of curcumin inside carbonate cross-linked cyclodextrin-based nanosponges and suggested the physical entrapment of crystalline curcumin in EDTA dianhydride. These findings were further investigated and supported by computational modeling.
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Curcumina , Ciclodextrinas , Nanoestructuras , Compuestos de Bifenilo , Carbonatos , Ciclodextrinas/química , Ácido Edético , Nanoestructuras/químicaRESUMEN
Background and purpose: Several pharmaceutical formulations were investigated to improve the solubility of 5-fluorouracil to enhance bioavailability and therapeutic efficacy. This study aimed to examine the potential use of cyclodextrin-based nanosponges for the incorporation of 5-fluorouracil and to investigate the use of different crosslinking agents on the properties of the resulting drug carrier. 5-Fluorouracil complexation with ß-cyclodextrin was also studied to explain the unexpected results of weak 5-fluorouracil incorporation in nanosponge. Experimental approach: Nanosponges were synthesized by crosslinking ß-cyclodextrin with two different crosslinkers; diphenyl carbonate and ethylenediaminetetraacetic dianhydride. The incorporation of 5-fluorouracil into ß-cyclodextrin and the prepared nanosponges were assessed by NMR, FTIR, PXRD, DSC, and TGA. In addition, an in vitro release study was carried out to evaluate the potential use of ß-cyclodextrin- based nanosponges as pharmaceutical formulations for 5-fluorouracil. Findings / Results: Physicochemical characterization of the dried formulations indicated the complexation of 5-fluorouracil with the ß-cyclodextrin polymer. Despite that, no clear manifestation of 5-fluorouracil encapsulation in the prepared ß-cyclodextrin-based nanosponge was detected. Furthermore, no significant differences were observed in the release profiles of 5-fluorouracil, ß-cyclodextrin complex, and ß- cyclodextrin-based nanosponge, suggesting weak complexation and instability in aqueous solutions. EDTA- crosslinked ß-cyclodextrin-based nanosponge showed a slight improvement in 5-fluorouracil solubility with a faster initial rate of 5-fluorouracil release. Conclusion and implications: This study suggested weak complexation between 5-fluorouracil and the ß- cyclodextrin polymer or nanosponges. Crosslinking of ß-cyclodextrin with EDTA dianhydride crosslinker showed an enhancement in 5-fluorouracil saturation solubility combined with a faster initial rate of drug release.
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A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a-3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k-3m. Thus, compounds 3k-3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.
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Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure-activity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules' potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.
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Anopheles , Insecticidas , Malaria , Animales , Proteínas Portadoras , Insecticidas/química , Insecticidas/farmacología , Hormonas Juveniles/farmacología , Larva , Simulación del Acoplamiento Molecular , Control de Mosquitos , Mosquitos Vectores , Pirimidinonas/farmacologíaRESUMEN
In a previous report, we described the discovery of (E)-5-((8-hydroxyquinolin-5-yl)diazenyl)-2-methylbenzenesulfonamide as a potent inhibitor of GLO-I enzyme with IC50 of 1.28 ± 0.12 µM. Herein, lead optimization of this compound was achieved through targeting the central zinc atom and hydrophilic amino acid residues in the active site of the enzyme. Among the synthesized compounds, compound TS010 showed the most potent inhibitory activity with IC50 of 0.57 ± 0.04 µM. Compound TS013 also showed comparable activity to that of the lead compound with IC50 of 1.14 ± 0.03 µM. Molecular docking studies disclosed the binding mode of the compounds inside the active side of GLO-I enzyme.
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Antineoplásicos , Lactoilglutatión Liasa , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lactoilglutatión Liasa/química , Lactoilglutatión Liasa/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The TOPK enzyme (also known as PBK) is a serine-threonine protein kinase that is rarely detected in normal tissues yet is found to be overexpressed and activated in a variety of cancers such as lung, colorectal, breast, and esophageal cancer. Its prevalence in cancerous cells is associated with their poor prognosis and responsiveness to treatment. This enzyme plays a vital role in cell division, specifically in regulating cytokinesis. Unlike drugs targeting early phases in mitosis, inhibition of cytokinesis by targeting biomolecules that are unique to multiplying cells poses no threat to the normal function of non-multiplying cells. Studies have shown that inhibition of cytokinesis is promising in suppressing the growth of proliferating cancerous cells as exemplified by the complete tumor regression seen with the suppression of TOPK. Herein, we report the identification of potent TOPK inhibitors with anticancer potential using a structure-based drug design approach. The only available crystal structure of TOPK corresponds to a double mutant (T9E and T198E) dimer with a distorted N-lobe conformation, thus 3D homology modeling was implemented to rebuild the enzyme's native conformation. The resulting refined model was used to generate 3D pharmacophore models for the virtual screening of small molecules databases. Retrieved hits were filtered, docked into the ATP binding site of the enzyme, rescored, and the binding free energies for the top consensually scoring hits were calculated. Consequently, 45 compounds were selected and their in vitro inhibitory activity against TOPK was tested revealing four potential hits with the most active compound having an IC50 of 3.85 µM. This compound will be chosen as a lead compound to synthesize analogs aiming to enhance potency and drug-like properties and to enrich the SAR data.
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Diseño de Fármacos , Simulación de Dinámica Molecular , Adenosina Trifosfato , Simulación del Acoplamiento Molecular , Proteínas Serina-Treonina QuinasasRESUMEN
A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.
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Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Indolizinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Antituberculosos/química , Indolizinas/química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/enzimologíaRESUMEN
The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (3a-3i) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively.To understand the mechanism of action of these compounds (3a-3i) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a, promising leads worthy of further optimisation.
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Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxadiazoles/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, arose at the end of 2019 as a zoonotic virus, which is the causative agent of the novel coronavirus outbreak COVID-19. Without any clear indications of abatement, the disease has become a major healthcare threat across the globe, owing to prolonged incubation period, high prevalence, and absence of existing drugs or vaccines. Development of COVID-19 vaccine is being considered as the most efficient strategy to curtail the ongoing pandemic. Following publication of genetic sequence of SARS-CoV-2, globally extensive research and development work has been in progress to develop a vaccine against the disease. The use of genetic engineering, recombinant technologies, and other computational tools has led to the expansion of several promising vaccine candidates. The range of technology platforms being evaluated, including virus-like particles, peptides, nucleic acid (DNA and RNA), recombinant proteins, inactivated virus, live attenuated viruses, and viral vectors (replicating and non-replicating) approaches, are striking features of the vaccine development strategies. Viral vectors, the next-generation vaccine platforms, provide a convenient method for delivering vaccine antigens into the host cell to induce antigenic proteins which can be tailored to arouse an assortment of immune responses, as evident from the success of smallpox vaccine and Ervebo vaccine against Ebola virus. As per the World Health Organization, till January 22, 2021, 14 viral vector vaccine candidates are under clinical development including 10 nonreplicating and four replicating types. Moreover, another 39 candidates based on viral vector platform are under preclinical evaluation. This review will outline the current developmental landscape and discuss issues that remain critical to the success or failure of viral vector vaccine candidates against COVID-19.
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With the current outbreak caused by SARS-CoV-2, vaccination is acclaimed as a public health care priority. Rapid genetic sequencing of SARS-CoV-2 has triggered the scientific community to search for effective vaccines. Collaborative approaches from research institutes and biotech companies have acknowledged the use of viral proteins as potential vaccine candidates against COVID-19. Nucleic acid (DNA or RNA) vaccines are considered the next generation vaccines as they can be rapidly designed to encode any desirable viral sequence including the highly conserved antigen sequences. RNA vaccines being less prone to host genome integration (cons of DNA vaccines) and anti-vector immunity (a compromising factor of viral vectors) offer great potential as front-runners for universal COVID-19 vaccine. The proof of concept for RNA-based vaccines has already been proven in humans, and the prospects for commercialization are very encouraging as well. With the emergence of COVID-19, mRNA-1273, an mRNA vaccine developed by Moderna, Inc. was the first to enter human trials, with the first volunteer receiving the dose within 10 weeks after SARS-CoV-2 genetic sequencing. The recent interest in mRNA vaccines has been fueled by the state of the art technologies that enhance mRNA stability and improve vaccine delivery. Interestingly, as per the "Draft landscape of COVID-19 candidate vaccines" published by the World Health Organization (WHO) on December 29, 2020, seven potential RNA based COVID-19 vaccines are in different stages of clinical trials; of them, two candidates already received emergency use authorization, and another 22 potential candidates are undergoing pre-clinical investigations. This review will shed light on the rationality of RNA as a platform for vaccine development against COVID-19, highlighting the possible pros and cons, lessons learned from the past, and the future prospects.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor and invade the human cells to cause COVID-19-related pneumonia. Despite an emphasis on respiratory complications, the evidence of neurological manifestations of SARS-CoV-2 infection is rapidly growing, which is substantially contributing to morbidity and mortality. The neurological disorders associated with COVID-19 may have several pathophysiological underpinnings, which are yet to be explored. Hypothetically, SARS-CoV-2 may affect the central nervous system (CNS) either by direct mechanisms like neuronal retrograde dissemination and hematogenous dissemination, or via indirect pathways. CNS complications associated with COVID-19 include encephalitis, acute necrotizing encephalopathy, diffuse leukoencephalopathy, stroke (both ischemic and hemorrhagic), venous sinus thrombosis, meningitis, and neuroleptic malignant syndrome. These may result from different mechanisms, including direct virus infection of the CNS, virus-induced hyper-inflammatory states, and post-infection immune responses. On the other hand, the Guillain-Barre syndrome, hyposmia, hypogeusia, and myopathy are the outcomes of peripheral nervous system injury. Although the therapeutic potential of certain repurposed drugs has led to their off-label use against COVID-19, such as anti-retroviral drugs (remdesivir, favipiravir, and lopinavir-ritonavir combination), biologics (tocilizumab), antibiotics (azithromycin), antiparasitics (chloroquine and hydroxychloroquine), and corticosteroids (dexamethasone), unfortunately, the associated clinical neuropsychiatric adverse events remains a critical issue. Therefore, COVID-19 represents a major threat to the field of neuropsychiatry, as both the virus and the potential therapies may induce neurologic as well as psychiatric disorders. Notably, potential COVID-19 medications may also interact with the medications of pre-existing neuropsychiatric diseases, thereby further complicating the condition. From this perspective, this review will discuss the possible neurological manifestations and sequelae of SARS-CoV-2 infection with emphasis on the probable underlying neurotropic mechanisms. Additionally, we will highlight the concurrence of COVID-19 treatment-associated neuropsychiatric events and possible clinically relevant drug interactions, to provide a useful framework and help researchers, especially the neurologists in understanding the neurologic facets of the ongoing pandemic to control the morbidity and mortality.
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The widespread of the COVID-19 disease, caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), had severely affected the entire world. Unfortunately, no successful vaccines or antiviral drugs are currently available which leaves the scientific community under huge pressure to tackle this pandemic. Among the identified promising druggable targets, specific to this virus, is the main protease (Mpro) enzyme, which is vital for viral replication, transcription and packaging within the host cells. In this study, selective inhibition of the Mpro was sought via thorough analysis of its available structural data in the Protein Data Bank. To this end, COVID-19 Mpro crystal complexes were explored and the key interacting residues (KIRs) within its active site, that are expected to be vital for effective ligand binding, were identified. Based on these KIRs, 3D pharmacophore models were generated and used in virtual screening of different databases. Retrieved hits were docked into the active site of the enzyme and their MM-PBSA based free binding energies were calculated. Finally, ADMET descriptors were calculated to aid the selection of top scoring hits with best ADMET properties. Nine compounds with different chemotypes were identified as potential Mpro inhibitors. Further, MD simulations of a virtual complex of Mpro with one of the promising hits revealed stable binding which is indicative of good inhibitory potential. The identified compounds in this study are expected to support the global drug discovery efforts in fighting against this highly contagious virus by narrowing the searchable chemical space for potential effective therapeutics.
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COVID-19 , Inhibidores de Proteasas , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , SARS-CoV-2RESUMEN
The glyoxalase system, particularly glyoxalase-I (GLO-I), has been approved as a potential target for cancer treatment. In this study, a set of structurally diverse polyphenolic natural compounds were investigated as potential GLO-I inhibitors. Ellagic acid was found, computationally and experimentally, to be the most potent GLO-I inhibitor among the tested compounds which showed an IC50 of 0.71 mmol L-1. Its binding to the GLO-I active site seemed to be mainly driven by ionic interaction via its ionized hydroxyl groups with the central Zn ion and Lys156, along with other numerous hydrogen bonding and hydrophobic interactions. Due to its unique and rigid skeleton, it can be utilized to search for other novel and potent GLO-I inhibitors via computational approaches such as pharmacophore modeling and similarity search methods. Moreover, an inspection of the docked poses of the tested compounds showed that chlorogenic acid and dihydrocaffeic acid could be considered as lead compounds worthy of further optimization.
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Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ácido Elágico/química , Ácido Elágico/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lactoilglutatión Liasa/antagonistas & inhibidores , Dominio Catalítico , Simulación por Computador , Ensayos Analíticos de Alto Rendimiento , Enlace de Hidrógeno , Lactoilglutatión Liasa/química , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Zinc/químicaRESUMEN
Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.
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Antituberculosos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Antituberculosos/química , Tuberculosis Extensivamente Resistente a Drogas/patología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Tuberculosis Resistente a Múltiples Medicamentos/patologíaRESUMEN
The enzyme glyoxalase-I (Glo-I) is an essential therapeutic target in cancer treatment. Significant efforts have been made to discover competitive inhibitors of Glo-I as potential anticancer agents. Herein, we report the synthesis of a series of diazenylbenzenesulfonamide derivatives, their in vitro evaluation against Glo-I and the resulting structure-activity relationships. Among the compounds tested, compounds 9h and 9j exhibited the highest activity with IC50 1.28 µM and 1.13 µM, respectively. Docking studies to explore the binding mode of the compounds identified key moieties that may contribute to the observed activities. The active compounds will serve as suitable leads for further chemical optimization.