Antimalarial Activities of a Therapeutic Combination of Azadirachta indica, Mangifera indica and Morinda lucida Leaves: A Molecular View of its Activity on Plasmodium falciparum Proteins.

BACKGROUND: The search for new antimalarial drugs remains elusive prompting research into antimalarial combinations from medicinal plants due to their cheapness, efficacy and availability. Azadirachta indica (AI), Morinda lucida (ML) and Mangifera indica (MI) have all been reported as potent antimalarial plants. PURPOSE: This study evaluated the efficacy of an antimalarial combination therapeutics prepared from leaves of AI, ML and MI using in vitro, in vivo and molecular methods. METHODS: Refined extracts of the plants combination was made by partitioning the aqueous extract of plants combinations (AI + MI, AI + ML, MI + ML, AI + MI + ML) using methanol and ethyl acetate consecutively. The resulting ethyl acetate partitioned fraction was evaluated for its antimalarial activity. Molecular docking and molecular dynamics simulation were employed to determine the possible mechanism of action of the constituent of the most active combination against four important P. falciparum proteins. RESULTS: The result revealed that the refined extract from combinations AI + ML and MI + ML at 16 mg/kg bodyweight have the highest chemo-suppressive effect of 90.7% and 91.0% respectively compared to chloroquine's 100% at 10 mg/kg. Also, refined extract from MI + ML combination improved PCV levels significantly (p < 0.05) compared to controls. Molecular docking revealed oleanolic acid and ursolic acid as multiple inhibitors of plasmepsin II, hiso-aspartic protease, falcipain-2 and P. falciparum Eonyl acyl-carrier protein reductase with relative stability during 100 ns of simulation. CONCLUSION: The study unveiled the potentials of ML and MI as good candidates for antimalarial combination therapy and further established their use together as revealed in folklore medicine.

Effect of Parquetina nigrescens (Afzel.) Leaves on Letrozole-Induced PCOS in Rats: a Molecular Insight into Its Phytoconstituents.

Polycystic ovarian syndrome (PCOS) is one of the common causes of female infertility in women of reproductive age. P. nigrescens is a plant used in the treatment of various diseases including menstrual disorders. This study investigated the effect of ethanolic extracts of P. nigrescens leaves on the estrous cycle, fasting blood glucose, and hormonal and lipid profile in letrozole-induced PCOS rats and also evaluated the molecular mechanism of the active constituents using computational methods. After the induction of PCOS with letrozole, rats were treated orally for 14 days with distilled water (1 mg/kg/day), clomiphene citrate (2 mg/kg/day), metformin (7.14 mg/kg/day), and ethanolic extract of P. nigrescens (50 and 100 mg). Thereafter, selected biochemical parameters were assayed to determine the extract's effect on the estrous cycle. Molecular docking and molecular dynamics simulation (MDS) were carried out to determine the binding affinity and relative stability of the ligand-receptor complexes. Letrozole-induced PCOS rats showed irregular estrous cyclicity, elevated (p > 0.05) triglycerides, low-density lipoprotein cholesterol (LDL), total cholesterol, insulin, testosterone, and luteinizing hormone (LH) concentration, low (p > 0.05) progesterone, low follicle-stimulating hormone (FSH), high-density lipoprotein cholesterol (HDL), and high fasting blood glucose concentration compared to that of the control group. The reproductive, biochemical, and structural alterations were reversed by the administration of ethanolic extract of P. nigrescens leaves (50 mg/kg) which restored the estrous cycle after 14 days of treatment. However, the ethanolic extracts of P. nigrescens (100 mg/kg) significantly increased (p > 0.05) FSH, HDL, and progesterone concentrations but decreased the LH, progesterone, and total cholesterol. Of all 44 compounds identified in GCMS analysis of an ethanolic extract of P. nigrescens leaves, only 2-ethylbutyl heptyl ester (CID 91705405) had a higher binding affinity for hormonal receptors and enzymes responsible for hepatic gluconeogenesis compared to standard drugs used in the study. CID 91705405 was also relatively stable over 100 ns of MDS. This compound is therefore revealed to have the potential to modulate both endocrine and metabolic pathways involved in PCOS. The ethanolic extract of P. nigrescens leaves can therefore be considered in the management/treatment of the reproductive and metabolic disorders related to PCOS subject to further experimental validation.

Computational studies on the cholinesterase, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) inhibitory activities of endophytes-derived compounds: towards discovery of novel neurotherapeutics.

Cholinesterases, beta-secretase 1 (BACE1) and monoamine oxidase (MAO) are significant in the etiology of neurodegenerative diseases. Inhibition of these enzymes is therefore a major strategy for the development of neurotherapeutics. Even though, this strategy has birthed some approved synthetic drugs, they are characterized by adverse effects. It is therefore, imperative to explore promising alternatives. Consequently, we assessed the inhibitory activities of some endophytes-derived compounds against selected targets towards discovery of novel neurotherapeutics. Standard inhibitors and 83 endophytes-derived compounds were docked against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), BACE 1 and MAO using AutodockVina while the molecular interactions between the selected targets and the compounds with notable binding affinity were viewed through Discovery Studio Visualizer. Druglikeness and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) and blood brain barrier (BBB) properties of the top 4 compounds were evaluated using the Swiss online ADME web tool and OSIRIS server; ligands-enzymes complex stability was assessed through molecular dynamics (MD) simulation. From the 83 compounds, asperflavin, ascomfurans C, camptothecine and corynesidone A exhibited remarkable inhibitory activity against all the four target enzymes compared to the respective standard inhibitors. However, only corynesidone A could transverse the BBB and predicted to be safe. MD simulation of the unbound and complexed enzymes with corynesidone A showed that the complexes were stable throughout the simulation time. Given the exceptional inhibitory activity of endophytes-derived corynesidone A against the four selected targets, its ability to permeate the BBB, excellent drugability properties as well as its stability when complexed with the enzymes, it is a good candidate for further studies towards development of new neurotherapeutics.Communicated by Ramaswamy H. Sarma.

Antidiarrheal activity of Bridelia ferruginea bark methanolic extract involves modulation ATPases in mice and inhibition of muscarinic acetylcholine receptor (M3) and prostaglandin E2 receptor 3 (EP3) in silico.

OBJECTIVES: Diarrhea, an abnormal state in which the individual has about three or more daily bowel movements, is now considered one of the most challenging global public health problems. Using plant products, such as Bridelia ferruginea is an alternative treatment option. The objective of this study was to investigate the antidiarrheal activity of B. ferruginea bark methanolic extract (BfME) and the mechanisms involved. METHODS: BfME antidiarrheal activity was evaluated in mice model of castor oil-induced diarrhea and enteropooling. To evaluate motility, gastrointestinal transit time was carried out using phenol red meal, while intestinal activities of selected ATPases were also evaluated. Furthermore, the active components in BfME were detected by GC-MS analysis, while molecular docking of the most abundant compounds with muscarinic acetylcholine receptor (M3) and prostaglandin E2 receptor 3 (EP3) were conducted. RESULTS: BfME at 400 and 800 mg/kg showed antidiarrheal activity by delaying onset of diarrhea, reduced gastrointestinal transit and increased intestinal activities of Na+ K+-ATPase, Ca2+ Mg2+-ATPase and Mg2+-ATPase. Molecular docking revealed that γ-sitosterol, α-amyrin, and stigmasterol have outstanding binding affinity for M3 and EP3. CONCLUSIONS: In view of these results, the observed antidiarrheal activity possibly occurs via the activation of ATPases activities and inhibition of M3 and EP3.

Computer-Aided Identification of Cholinergic and Monoaminergic Inhibitory Flavonoids from Hibiscus sabdariffa L.

BACKGROUND: The reduced levels of acetylcholine and dopamine lead to Alzheimer's disease (AD) and Parkinson's disease PD, respectively, due to the action of cholinesterase and monoamine oxidase B. METHODS: Therapeutic options for AD and PD involve respective cholinergic and monoaminergic inhibitors, and considering the adverse outcomes of cholinergic- and monoaminergic- inhibitory therapeutics, phytoconstituents may be promising alternatives. Reports have shown that different extracts of the calyx of Hibiscus sabdariffa exhibit anticholinesterase and monoamine oxidase B inhibitory properties with the potential to delay and prevent the development of AD and PD. However, there is limited knowledge on the multitarget cholinergic and monoaminergic inhibitory activities of individual compounds in this plant. Computational methods were used to identify the specific compounds responsible for the observed cholinergic and monoaminergic inhibitory activities of the H. sabdariffa calyx extracts. RESULTS: Results confirm that three flavonoids: delphinidin-3-sambubioside, kaempferol-3-O-rutinoside and quercetin-3-rutinoside showed strong binding affinity with acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B while the observed stability of the ligands-enzymes complexes over the MD simulation time suggests their cholinergic and monoaminergic inhibitory properties. CONCLUSION: The three flavonoids may be responsible for the reported anticholinergic and monoaminergic inhibitory potentials of H. sabdariffa extracts and could be enlisted as multi-target inhibitory agents for cholinesterases and monoamine oxidase B.

Evaluation of the inhibitory potentials of selected compounds from Costus spicatus (Jacq.) rhizome towards enzymes associated with insulin resistance in polycystic ovarian syndrome: an in silico study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a chronic endocrine disorder prevalent in premenopausal women and is characterized by a range of physiological and biochemical abnormalities which may include reproductive, endocrine, and metabolic alterations such as insulin resistance. Insulin resistance is the hallmark of PCOS as it predisposes the affected subjects to a higher risk of impaired glucose tolerance and type 2 diabetes mellitus (T2DM). In this study, the inhibitory activities of phytosterols and saccharides from aqueous extract of Costus spicatus rhizome were investigated against phosphoenolpyruvate carboxykinase (PEPCK), α-amylase, ß-glucosidase, and fructose 1,6-biphosphatase (FBPase) in silico as potential novel therapeutic targets for T2DM-associated-PCOS. Phytochemical constituents of the plant were determined using gas chromatography-mass spectrophotometry (GC-MS), while molecular docking of the compounds with PEPCK, α-amylase, ß-glucosidase, and FBPase was conducted using Vina. Thereafter, the binding modes were determined using Discovery Studio Visualizer, 2020. RESULTS: GCMS analysis of an aqueous extract of Costus spicatus rhizome revealed the presence of three compounds with a higher binding affinity for all enzymes studied compared to metformin. The compounds also interacted with key amino acid residues crucial to the enzyme's activities. This study identified Lyxo-D-manno-nononic-1,4-lactone as potential multi-target inhibitors of PEPCK, α-amylase, ß-glucosidase, and FBPase with reasonable pharmacokinetic properties and no significant toxicity. CONCLUSION: These compounds can be explored as potential therapeutic agents for the management of insulin resistance in PCOS, subject to further experimental validation.

QSAR modeling and pharmacoinformatics of SARS coronavirus 3C-like protease inhibitors.

The search for effective treatment against novel coronavirus (COVID-19) remains a global challenge due to controversies on available vaccines. In this study, data of SARS coronavirus 3C-like protease (3CLpro) inhibitors; a key drug target in the coronavirus genome was retrieved from CHEMBL database. Quantitative Structure-Activity Relationship (QSAR) studies, Molecular docking, Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) and molecular dynamics simulation (MDS) were carried out using these 3CLpro inhibitors. QSAR model constructed using the data had correlation coefficient R2 value of 0.907; cross-validated correlation coefficient Q2 value of 0.866 and test set predicted correlation coefficient R2pred value of 0.517. Variance inflation factor (VIF) values for descriptors contained in the model ranged from 1.352 to 1.68, hence, these descriptors were orthogonal to one another. Therefore, the model was statistically significant and can be used to screen and design new molecules for their inhibitory activity against 3CLpro. Molecular docking showed that seven of the compounds (inhibitors) used in the study had a remarkable binding affinity (-9.2 to -10.3 kcal/mol) for 3CLpro. ADMET study revealed that five (CHEMBL Accession IDs 19438, 196635, 377150, 208763, and 210097) of the seven compounds with good binding ability obeyed Lipinski's rule of five. Hence, they were compounds with drug-like properties. MDS analysis revealed that 3CLpro-compound 21, 3CLpro-compound 22, 3CLpro-compound 40 complexes are very stable as compared to the reference 3CLpro-X77 complex. Therefore, this study identified three potent inhibitors of 3CLpro viz. CHEMBL194398, CHEMBL196635, and CHEMBL210097 that can be further explored for the treatment of COVID-19.

BACE1 and cholinesterase inhibitory activities of compounds from Cajanus cajan and Citrus reticulata: an in silico study.

Alzheimer's disease (AD) is one of the major neurodegenerative diseases whose underlying risk factors are yet to be fully understood. However, reduced cellular level of cholinesterase, as well as formation and deposition of amyloid plaques (Aß) are thought to play critical roles in the pathogenesis of AD. Therefore, increases in cholinergic transmitter levels via cholinesterase (ChE) inhibitors as well as inhibition of amyloid plaques formation and aggregation via beta secretase-1 (BACE1) inhibitors have been proposed as treatment for this disease. This study was aimed at investigating the BACE1 and ChE inhibitory properties of compounds from Cajanus cajan and Citrus reticulata based on their traditional connection with the management of neurodegenerative diseases, coupled with their protective effects on chemical-induced cognitive impairment. Using in silico methods, one hundred and nineteen compounds from C. cajan and C. reticulata were docked with acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1 using Vina. Molecular interactions of the top-ranked compounds for the 3 protein targets were viewed with Discovery Studio, followed by characterization of their ADME properties using the Swiss online ADME web tool. Among the one hundred and ninety nine compounds screened, 3 compounds, genistin (76), naphthalen-2-yl-acetic acid, 6-hydroxy-6-methyl-cyclodecyl ester (94) and vitexin (119) have remarkable binding affinity for the three protein targets and passed the oral drugability test, while only naphthalen-2-yl-acetic acid, 6-hydroxy-6-methyl-cyclodecyl ester (94) exhibited BBB permeation property. Genistin and vitexin from C. cajan and naphthalen-2-yl-acetic acid, 6-hydroxy-6-methyl-cyclodecyl ester from C. reticulata possibly contributed, at least in part, to the neurotherapeutic potentials of these plants.

A Computational Approach to Investigate the HDAC6 and HDAC10 Binding Propensity of Psidium guajava-derived Compounds as Potential Anticancer Agents.

BACKGROUND: Different parts of Psidium guajava are consumed as food and used for medicinal purposes around the world. Although studies have reported their antiproliferative effects via different biochemical mechanisms, their modulatory effects on epigenetic modification of DNA molecules via histone deacetylases (HDACs) are largely unknown. OBJECTIVE: This study was carried out to investigate the histone deacetylase 6 (HDAC6) and histone deacetylase 10 (HDAC10) binding propensity of guava-derived compounds, using in silico methods, in other to identify compounds with HDAC inhibitory potentials. METHODS: Fifty-nine guava-derived compounds and apicidin, a standard HDAC inhibitor, were docked with HDAC6 and HDAC10 using AutodockVina after modeling (SWISS-MODEL server) and validating (ERRAT and VERIFY-3D) the structure of HDAC10. Molecular interactions between the ligands and the HDACs were viewed with Discovery Studio Visualizer. Prediction of binding sites, surface structural pockets, active sites, area, shape and volume of every pocket and internal cavities of proteins was done using Computed Atlas of Surface Topography of proteins (CASTp) server, while absorption, distribution, metabolism, and excretion (ADME) study of notable compounds was done using Swiss online ADME web tool. RESULTS: 2α-hydroxyursolic acid, asiatic acid, betulinic acid, crategolic acid, guajadial A and B, guavacoumaric acid, guavanoic acid, ilelatifol D, isoneriucoumaric acid, jacoumaric acid, oleanolic acid, psiguadial A, B, and C demonstrated maximum interaction with the selected HDACs. ADME studies revealed that although isoneriucoumaric and jacoumaric acid ranked very high as HDAC inhibitors, they both violated the Lipinski's rule of 5. CONCLUSION: This study identified 13 drugable guava-derived compounds that can be enlisted for further studies as potential HDAC6 and HDAC10 inhibitors.

Phytosterols and triterpenes from Morinda lucida Benth (Rubiaceae) as potential inhibitors of anti-apoptotic BCL-XL, BCL-2, and MCL-1: an in-silico study.

Deregulation of the normal cellular apoptotic function is a fundamental element in the etiology of most cancers and the anti-apoptotic B cell lymphoma 2 (BCL­2) protein family is known to play crucial role in the regulation of this function. Overexpression of this protein family has been implicated in some cancers, such that agents that could inhibit their over-activity are now being explored for anticancer drug development. A number of studies have revealed the anticancer potential of Morinda lucida-derived extracts and compounds. In search of more inhibitors of this anti-apoptotic protein family from plant resources, 47 compounds, identified in Morinda lucida Benth (Rubiaceae) were screened for their inhibitory activities against BCL-XL, BCL-2, and MCL-1 by molecular docking using BINDSURF, while binding interactions of the top compounds were viewed with PyMOL. Druglikeness and Absorption-Distribution-Metabolism-Excretion (ADME) parameters of the top 6 compounds from docking study were evaluated using SuperPred webserver. Results revealed that out of the 47 compounds, 2 triterpenes (ursolic acid and oleanolic acid) and 4 phytosterols (cycloartenol, campesterol, stigmasterol, and ß-sitosterol) have higher binding affinities for the selected BCL-2 proteins, compared to known standard inhibitors; these compounds also fulfill oral drugability of Lipinski rule of five. Therefore, since these Morinda lucida-derived phytosterols and triterpenes show high binding affinity toward the selected anti-apoptotic proteins and exhibited good drugability characteristics, they qualify for further study on drug development against cancers characterized by overexpression of this family of protein.

Phytosterols and triterpenes from Morinda lucida Benth. exhibit binding tendency against class I HDAC and HDAC7 isoforms.

The important role of histone deacetylases (HDACs) in the development of cancer has been demonstrated by various studies. Thus targeting HDACs with inhibitors is a major focus in anticancer drug research. Although few synthetic HDAC inhibitors (HDIs) have been approved for cancer treatment, they have significant undesirable side effects. Therefore emphases have been placed on natural HDIs as substitutes for the synthetic ones. In a bid to identify more HDIs, this study evaluated the binding tendency of compounds derived from Morinda lucida Benth. towards selected HDACs for the discovery of potent HDIs as potential candidates for anticancer therapeutics, based on the report of anticancer potentials of Morinda lucida-derived extracts and compounds. Givinostat and 49 Morinda-lucida derived compounds were docked against selected HDAC isoforms using AutodockVina, while binding interactions were viewed with Discovery Studio Visualizer, BIOVIA, 2016. Druglikeness and Absorption-Distribution-Metabolism-Excretion (ADME) parameters of the top 7 compounds were evaluated using the Swiss online ADME web tool. The results revealed that out of the 49 compounds, 3 phytosterols (campesterol, cycloartenol, and stigmasterol) and 2 triterpenes (oleanolic acid and ursolic acid) exhibited high HDAC inhibitory activity compared to givinostat. These 5 compounds also fulfill oral drugability of Lipinski rule of five. Morinda lucida-derived phytosterols and triterpenes show high binding tendency towards the selected HDACs and exhibited good drugability characteristics and are therefore good candidates for further studies in the search for therapies against abnormalities linked with over-activity of HDACs.

In vivo antimalarial activity and toxicological effects of methanolic extract of Cocos nucifera (Dwarf red variety) husk fibre.

OBJECTIVE: Phytochemical constituents as well as antimalarial and toxicity potentials of the methanolic extract of the husk fibre of Dwarf Red variety of Cocos nucifera were evaluated in this study. METHODS: The dried powdered husk fibre was exhaustively extracted with hexane, ethyl acetate and methanol successively and the methanolic extract was screened for flavonoids, phenolics, tannins, alkaloids, steroids, triterpenes, phlobatannins, anthraquinones and glycosides. A 4-day suppressive antimalarial test was carried out using Plasmodium berghei NK65-infected mice, to which the extract was administered at doses of 31.25, 62.5, 125, 250 and 500 mg/kg body weight (BW). Toxicity of the extract was evaluated in rats using selected hematological parameters and organ function indices after orally administering doses of 25, 50 and 100 mg/kg BW for 14 d. RESULTS: Phytochemical analysis revealed the presence of alkaloids, tannins, phenolics, saponins, glycosides, steroids and anthraquinones in the extract. Moreover, the extract reduced parasitemia by 39.2% and 45.8% at doses of 250 and 500 mg/kg BW respectively on day 8 post-inoculation. Various hematological parameters evaluated were not significantly altered (P>0.05) at all doses of the extract, except red blood cell count which was significantly elevated (P<0.05) at 100 mg/kg BW. The extract significantly increased (P<0.05) urea, creatinine, cholesterol, high-density lipoprotein-cholesterol and bilirubin concentrations in the serum as well as atherogenic index, while it reduced albumin concentration significantly (P<0.05) at higher doses compared to the controls. Alanine aminotransferase activity was reduced in the liver and heart significantly (P<0.05) but was increased in the serum significantly (P<0.05) at higher doses of the extract compared to the controls. CONCLUSION: The results suggest that methanolic extract of the Dwarf red variety has partial antimalarial activity at higher doses, but is capable of impairing normal kidney and liver function as well as predisposing subjects to cardiovascular diseases.

In vivo antimalarial activity and toxicological effects of methanolic extract of Cocos nucifera (Dwarf red variety) husk fibre / 中西医结合学报

Phytochemical constituents as well as antimalarial and toxicity potentials of the methanolic extract of the husk fibre of Dwarf Red variety of Cocos nucifera were evaluated in this study.