Current Enzyme Inhibition - Volume 18, Issue 2, 2022

Background: Compromises in the cellular enzymatic defense barrier can increase the duration of exposure to electrophiles and the severity of toxicity they may incur. Objective: In this mini-review, we discuss the inhibition of the enzymatic defense systems by different antidepressants commonly prescribed worldwide as well as herbal products used for various forms of depression. Methods: Our work primarily focused on the interactions of two prominent biotransformation enzyme systems, namely glutathione S-transferases and cholinesterases, with tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and hypericin. Results: The antidepressants exert considerable inhibitory effects against glutathione -transferases and butyrylcholinesterase. Conclusion: The outcomes of available published studies and their implications for health and disease are discussed here in detail.

Poly [ADP-ribose] polymerase-1 [PARP-1] is a chromatin-bound nuclear enzyme that gets activated by DNA damage. It facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Increased PARP-1 expression is observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. PARP-1 interacts directly and indirectly with various oncogenic proteins and regulates several transcription factors, thereby modulating carcinogenesis. There is a lot of pre-clinical and clinical data supporting the use of PARP-1 inhibitors [PARP-1i] in cancers that express homologous recombination deficiencies like mutations within the BRCA-1/2 genes. Therapeutic inhibition of PARP-1 is therefore perceived as a promising anticancer strategy, and numerous PARP-1i are currently under development and clinical evaluation. Currently, there are 4 FDA-approved PARP-1i products on the market, and a few more are in the last stage of clinical development. All the molecules are non-selective PARP-1i. While giving promising results, PARP-1i have their own disadvantages, like safety problems, resistance, etc. Looking at the success rate of PARP-1i in various solid tumours, there is a need for novel and selective PARP-1i. In this review, we discuss various aspects related to PARP-1i, like recent developments, overcoming resistance, and selectivity criteria of new molecules for potential PARP-1i.

Background: Diabetes has become a major health problem due to its high prevalence, morbidity, and mortality rate. Reducing postprandial hyperglycemia has become the main target in the treatment of diabetes mellitus. So, developing new drugs with fewer side effects has been a major priority. Objective: The main objective of this study is to investigate total phenolic and flavonoid content, antioxidant activity, α-glucosidase, and α-amylase inhibition activity of Persea Americana Mill (avocado) pulp and seed. Methods: The α-glucosidase and α-amylase inhibition activity were performed using substrates PNPG and CNPG3, respectively. DPPH free radical scavenging assay was used to perform the antioxidant activity. The total phenolic content was estimated using folin-ciocalu’s reagent. Likewise, the aluminium trichloride method was applied to find out the total flavonoid content. Results: The crude methanolic extract of avocado seed revealed potent α-glucosidase inhibition activity with an IC50 1.959±0.93μg/mL followed by the avocado pulp 308±2.36μg/mL. Similarly, the IC50 for the α-amylase inhibition activity of avocado seed was found to be 120.3±1.382μg/mL. In addition, the avocado pulp and seed revealed a significant antioxidant activity with IC50 values of 75.01±0.72μg/mL and 6.445±0.62μg/mL, respectively, compared to the standard quercetin 1.525±0.5μg/mL. The total phenolic content of avocado pulp and the seed was reported as 7.031±2.87 mg of GAE/g, and 142.96±1.589 mg of GAE/g, respectively. Similarly, the total flavonoid content of avocado pulp and the seed was found to be 6.313±1.301 mg of QE/g and 48.696±0.110 mg of GAE/g, respectively. Conclusion: The avocado seed of Nepali origin was found to inhibit the digestive enzyme significantly. These findings indicate that avocado fruit of Nepali origin has the potential to develop as an alternative food therapy for diabetic patients. Further research is required to find out the inhibitor compounds.

Background: Calotropis gigantea (Asclepiadaceae), a wildly growing plant, has several purported therapeutic characteristics and treats toothache and earache, sprains, anxiety, pain, epilepsy, and mental disorders. Objective: The purpose of this study was to determine the in vitro antioxidant and in vivo hepatoprotective capabilities of a methanolic extract of Calotropis gigantea leaves (CGL) against carbon tetrachloride-induced liver injury in rats. Methods: The Sprague Dawley rats (180-250 g) were used for the current study. The hepatoprotective activity of CGL was determined by estimating the different biochemical parameters like SGOT, SGPT, ALP, bilirubin, and in vivo antioxidant parameters like LPO, GSH, SOD, and CAT in different animal groups. We have also investigated the inhibitory potential of some significant chemical constituents of CGL on CYP2E1 through molecular docking. Results: In vivo hepatoprotective studies indicate that the CGL extract administration caused a significant reduction [at 200 mg, SGOT (110.16 IU/L), SGPT (101.33 IU/L), ALP (186.66 IU/L), bilirubin (1.1 mg/dl), and LPO (6.933 M/mg protein)] and elevation [GSH (14.051 M/mg protein), SOD (257.5%), and CAT (15.975 μM)] in enzyme activity in a dose-dependent manner. Unfortunately, CGL extract has not shown a more potent activity than the standard drug Silymarin. All the phytoconstituents have shown potent binding affinity with CYP2E1 compared to the native ligand. Amongst all the phytoconstituents, Medioresinol was the most active and potent molecule that has developed compelling interactions with CYP2E1. Conclusion: From free radical scavenging activity, it was concluded that CGL extract exerts more scavenging activity than ascorbic acid, which indicates a high level of polyphenols and tocopherols and also exhibited in vivo hepatoprotective activity. From the molecular docking, it has been concluded that Calotropis gigantea can potentially inhibit CYP2E1 and prevent the generation of free radicals, which will ultimately reduce oxidative stress and associated diseases.

Aims: This study aimed at identifying promising breast cancer inhibitors through in vitro and in silico studies. Background: Piper betel. L. is a traditional herb used for varied ailments. Objective: The present study is designed to evaluate the anti-carcinogenic potency of HC against the MCF-7 cell line by in vitro analysis. Further in silico examination was performed to detect and formulate protein-ligand complex of HC using molecular docking technique. Methods: In vitro study was conducted using MTT assay and microscopic examinations to determine the cell viability and morphological changes in MCF-7 cells. In silico, scrutiny was performed using virtual screening, Docking, ADME, DFT analysis, MMGBSA, and molecular dynamic simulation to evaluate hydroxychavicol stability. Results: HC showed an outstanding anti-cancer potential, with dose- and time-dependent patterns in MTT assay and through the fluctuating organization of MCF-7 cells. In silico analysis showed that the selected lead compound-complex exhibited good stability and was a highly potent inhibitor against the target breast cancer protein. Conclusion: This study confirmed that HC might be an alternate potential inhibitor against breast cancer.

Background: The traditional pharmacopoeia is full of potential resources for molecules with therapeutic effects involving the inhibition of enzymes linked to some diseases. Objective: This work aimed to test in vitro neuroprotective activity against Alzheimer's disease (AD) combined with the antioxidant effect of root extracts obtained by water, water/methanol, and ethyl acetate of the endemic Arctium minus. subsp. Atlanticum, a native of Algeria. Methods: The different extracts of the root of the studied plant were obtained by decoction or maceration. The inhibitory effect of acetyl/butyrylcholinesterase (AChE/BChE) was achieved by a colorimetric method. Similarly, the antioxidant activity was measured based on several mechanisms: 1, 1- diphenyl-2-picryl-hydrazyl (DPPH) and galvinoxyl (GOR) radicals free scavenging assays, β-carotene bleaching inhibition activity, and cupric ion reducing antioxidant capacity (CUPRAC). Results: In the various tests carried out, the ethyl acetate extract (EAE) possessed the most powerful antioxidant and anticholinesterase activities compared to the other samples. The IC50 and A0.5 values of DPPH, GOR, β-carotene, CUPRAC, anti-AChE, and anti-BChE assays were 69.45±5.49, 28.87±0.18, 121.58±16.76, 37.41±1.59, 265±21, and 240±6.3 μg / mL, respectively. Likewise, a correlation could be deduced between the type of extract and the potent antioxidant/anticholinesterase potential. Conclusion: This work examines for the first time the anticholinesterase potential combined with the antioxidant effect of Algerian Arctium minus. subsp. atlanticum. This association between the two effects could be effective in the fight against AD, and therefore, the use of this natural resource may be possible in combating this aspect of neurodegeneration.

Introduction: An efficient one-pot synthesis of 2-alkylidene/arylidene derivatives was reported from active methylene compounds such as malononitrile/ethyl cyanoacetate/5-methyl-2,4- dihydro-3H-pyrazol-3-one and aldehydes in the presence of 10 mol% of L-proline (ethanol at room temperature). Methods: All derivatives were obtained in good to excellent yields. The structures of the synthesized compounds were confirmed from their FTIR (Fourier-transform infrared spectroscopy), ¹H-NMR (Proton nuclear magnetic resonance), and mass spectroscopy. The importance of these compounds is predicted from their SAR (structure-activity relationship) study. Moreover, these newer compounds were further docked into various therapeutic targets of the SARS-CoV-2 (severe acute respiratory syndromerelated coronavirus) virus. Results: Results from our molecular docking suggest that these compounds have good inhibitory properties on the SARS- CoV-2 virus. Conclusion: L-proline (bifunctional organic catalyst) is found to be the best catalyst for the synthesis of different condensed products from active methylene compounds and aldehydes.