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.

Nigerian antimalarial plants and their anticancer potential: A review.

Cancer is a leading cause of death globally, while malaria is the leading cause of death from parasitic diseases in Nigeria. Historically, plant remedies have been used to manage both cancer and malaria. Interestingly, the possibility of treating cancer with antimalarial remedies has long been reported, even though the two diseases appear to have little in common. However, a body of research has indicated the potential anticancer activity of both synthetic and nature-derived antimalarials. In Nigeria, over 100 plants are used for the management of malaria, but little is known for their potential role in combatting cancer. Therefore, this review is to highlight the documented anticancer activities of plants used to treat malaria in Nigeria, with the goal of supporting anticancer drug discovery. Scientific databases were used to search for antimalarial plants using selected keywords. Of over 100 plants used to treat malaria in Nigeria, 56 have documented anticancer properties, containing alkaloids, flavonoids, tannins, terpenes, terpenoids, quinones, anthraquinones, saponins, steroids, sterols, organosulfur compounds and other polyphenols as the major bioactive components. The major mechanisms of anticancer activity include induction of apoptosis and autophagy, arrest of cell growth, generation of reactive oxygen species and inhibition of angiogenesis. However, mechanistic and clinical investigations of the anticancer properties of most of these plants are still lacking. Notwithstanding, the huge anticancer potential uncovered by the in vitro or in vivo studies and a few clinical studies, Nigerian antimalarial plants may provide a valuable resource, ready to be harnessed for anticancer drug development.

Effects of Cysteine-Stabilised Peptide Fraction of Aqueous Extract of Morinda lucida Leaf on Selected Cardiovascular Disease Indices in Mice.

This study evaluated the effects of cysteine-stabilised peptide fraction (CSPF) of aqueous extract of Morinda lucida leaf on selected cardiovascular disease indices in mice. Sixty adult Swiss Albino mice were randomly divided into 6 groups (n = 10). Group A served as control and received 5% DMSO. Half of the mice in groups B, C, D, E and F received 31.25, 62.5, 125, 250, and 500 mg/kg body weight of CSPF respectively for 7 days while the other half received the various doses for 28 days. After the experimental period, selected cardiovascular disease indices were determined in the mice. The results revealed that CSPF significantly reduced (p < 0.05) atherogenic index, plasma concentrations of total cholesterol and LDL-cholesterol but significantly increased (p < 0.05) plasma HDL-cholesterol concentration at higher doses after 28 days of administration. Plasma lactate dehydrogenase, aspartate aminotransferase and alkaline phosphatase activities were not significantly altered (p > 0.05) at all doses of the CSPF after 7 and 28 days of administration  compared to controls. After 7 days of CSPF administration, the activities of heart Ca2+, Mg2+-ATPase and Na+-K+-ATPase were not significantly altered (p > 0.05) but heart Mg2+-ATPase activity was significantly increased (p < 0.05) at 250 mg/kg body weight compared to controls. Also, 28 days of CSPF administration at all doses had no significant effect (p > 0.05) on the activities of heart Mg2+-ATPase and Na+-K+-ATPase of mice compared to controls but heart Ca2+-Mg2+-ATPase activity was significantly increased (p < 0.05) at the highest dose with no significant alteration (p > 0.05) at other doses compared to controls. Generally, CSPF administration had no significant effect (p > 0.05) on haematological parameters after 7 and 28 days. These results suggest that CSPF may not predispose subjects to cardiovascular diseases.

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.

Effects of Cysteine-stabilized Peptide Fraction of Morinda lucida Leaf on Selected Kidney Function Indices in Mice.

OBJECTIVE: This study evaluated the effect of cysteine-stabilized peptide fraction (CSPF) of Morinda lucida leaf on selected kidney function indices in mice. METHODS: Sixty mice were assigned into six groups. Group A served as the control while groups B, C, D, E and F received 31.25, 61.5, 125, 250, and 500 mg/kg body weight of CSPF respectively for 7 or 28 days. RESULTS: Administration of CSPF for 7 and 28 days caused no significant (p>0.05) alteration in kidney-body weight ratio, plasma concentrations of the selected electrolytes, urea and creatinine at all doses compared to controls. However, plasma uric acid concentration was significantly increased (p<0.05) after administration of CSPF for 7 days at doses of 125 and 500 mg/kg body weight while it was significantly reduced (p<0.05) after administration for 28 days at doses higher than 31.25 mg/Kg body weight compared to controls. The activities of Ca2+, Mg2+-ATPase and Na+, K+-ATPases in the kidney and the histology of the kidney remained unaltered (p>0.05) throughout the experimental period compared to controls. CONCLUSION: CSPF may adversely affect uric acid metabolism after prolonged administration.