Descriptor-free QSAR: effectiveness in screening for putative inhibitors of FGFR1.

The long short-term memory (LSTM) algorithm has provided solutions to the limitations of the descriptors-utilizing QSAR models in drug design. However, the direct application of LSTM remains scarce. The effectiveness of a descriptor-free QSAR (LSTM-SM) in modeling the FGFR1 inhibitors dataset while comparing with two conventional QSAR using descriptors (126 bits Morgan fingerprint and 2 D descriptors respectively) as a baseline model was investigated in this study. The validated descriptor-free QSAR model was thereafter used to screen for active FGFR1 inhibitors in the ChemDiv database and subjected to molecular docking, induced-fit docking, QM-MM optimization, and molecular dynamics simulations to filter for compounds with high binding affinity and suggest the putative mechanism of inhibition and specificity. The LSTM-SM model performed better than conventional QSAR; having accuracy, specificity, and sensitivity of 0.92, model loss of 0.025, and AUC of 0.95. Fifteen thousand compounds were predicted as actives from the ChemDiv database and four compounds were finally selected. Of the four, two showed putatively effective binding interactions with key active site residues. Molecular dynamics simulations on these compounds in complex with the receptor further give insight into the conformational dynamics of each compound bounded to the receptor. The complexes formed are stable and exhibit a similar degree of compactness. Our findings predicted the advent of self-feature extracting machine learning algorithms of compounds, and have provided the possibility of better predictive model quality that is not necessarily limited by compound descriptors. The putative FGFR1 inhibitors, with their mechanism of inhibition and specificity, were elucidated using this approachCommunicated by Ramaswamy H. Sarma.

Neuro-pharmacological potentials of Buchholzia coriacea (Engl.) seeds in laboratory rodents.

BACKGROUND: Buchholzia coriacea, taken by elderly, has phytochemicals that have neuro-active metabolites, and the folklore documented its use in neuro-behavioural despairs. OBJECTIVE: This study was conducted to investigate the neuro-pharmacological potentials of Buchholzia coriacea (MEBC) seed extract in the laboratory rodents. METHODOLOGY: Methanol extract of the seeds on B. coriacea (MEBC) was evaluated for its antidepressant (Forced Swimming Test and Tail Suspension Test), anxiolytic (Light-Dark Test, Hole Board Test and Elevated Plus Maze), antinociceptive (Hot-Plate and Tail Flick test) and motor coordination (Rota Rod) functions in mice. RESULTS: Our findings showed antidepressant activity (P < 0.05) of MEBC that is dose-dependent. Secondly, MEBC showed significant anxiolytic property that is comparable with the standard drug (diazepam). Furthermore, MEBC significantly prolonged the latency on hot-plate and tail flick responses when compared with the control (P < 0.05). Finally, MEBC significantly prolonged mice endurance time (P < 0.05) on a revolving Rota rod. The results suggest antidepressant, anxiolytic and analgesic potentials of MEBC. CONCLUSION: Buchholzia coriacea may have a stabilizing effect on the motor activity and MEBC probably contains secondary metabolites with some therapeutic effects on neuro-physiological disorders like depression, anxiety and pain.

Modulation of opening of rat liver mitochondrial membrane permeability transition pore by different fractions of the leaves of Cnestis ferruginea. D.C.

BACKGROUND: Increased attention is now directed towards the search for novel naturally occurring anticancer agents that can induce mitochondrial membrane permeability transition (MMPT) pore opening and cell death as a chemotherapeutic mechanism to combat cancer incidence. AIM: The inductive effects of partially purified fractions of leaves of Cnestis ferruginea- on rat liver MMPT pore opening was investigated. METHOD: De-fatted methanol extract of leaves of Cnestis ferruginea was partitioned between water, chloroform, ethylacetate, or butanol separately in succession. The extract solutions were concentrated at 40 degrees C to obtain water (WF), chloroform (CF), ethylacetate (EF) and butanol (BF) fractions. The effects of these fractions (0.2- 1.4 mg/ml) on MMPT pore opening or mitochondrial swelling in the presence and absence of calcium were evaluated The effects of these fractions on the rat liver mitochondrial F0F1-ATPase activity were also assessed. RESULTS: Ca(2+)-induced MMPT pore opening was inhibited by 1 mg/ml each of MECF, CF, BF, WF and EF by 75.0%, 83.0%, 88.0%, 68.0%, and 71.0%, respectively and compared with the effect of spermine, a standard inhibitor. However, in the absence of Ca2+, the fractions significantly induced MMPT pore opening in intact mitochondria by 7.0, 5.7, 0.7, 4.8, 10.9 folds, respectively. In normal rat liver mitochondria, F1F0-ATPase activity was stimulated maximally by MECF, CF, EF, BF and WF by 4.7, 12.7, 1.6, 3.6 and 1.5 folds, respectively, thus indicating that the chloroform fraction is the most potent and therefore contains the active principle in the plant. CONCLUSION: The present study revealed that the leaves of Cnestis ferruginea contain bioactive substances that induced mitochondrial membrane permeability transition and activated the specific activity of F0F1 ATPase. Thus, suggesting strongly that these bioactive agents may serve as a useful chemotherapeutic strategy in cancer therapy.

Sulphadoxine-pyrimethamine alters the antioxidant defense system in blood of rabbit.

Sulphadoxine-pyrimethamine (SP) despite reported resistance remains an important drug of choice for the treatment and control of malaria in most endemic areas. Exacerbation of intra-erythrocytic oxidative stress might contribute to the process of elimination of malaria parasites in the body. The effect of treatment with SP on the antioxidant defense system was investigated using rabbit as a model. Ten male rabbits were divided into two groups of five animals each. The first group was administered with normal saline and served as control. The second group received a single dose of SP (26.25mg/kg body weight). Blood samples were collected before and at 6, 12 and 24 h after drug administration. Activity of cellular enzymatic antioxidants, superoxide dismutase (SOD) and catalase (CAT), and level of reduced glutathione (GSH) were assayed using standard spectrophotometric methods. Serum lipid peroxidation was assessed by the formation of thiobarbituric acid reactive species (TBARS) while protein content was assayed by the method of Lowry et al., 1951. SOD activity was observed to increase progressively by 4.9, 63.4 and 120.8% at 6, 12 and 24 h respectively, after drug administration. Similarly, CAT activity increased by 44.5, 82.6 and 116.3% at 6, 12 and 24 h, respectively. TBARS level also increased significantly by 45.5, 118.2 and 186.4%, respectively. However, the level of GSH decreased by 41.9% at 6 h and remained so up till the 12 h, but by 24 h after drug administration, the level of the thiol substance has increased considerably up to 48.4% above the baseline level. SP treatment altered the antioxidant defense system in blood and may therefore induce oxidative stress by generating reactive oxygen species. This might play significant role in the therapeutic and adverse effects associated with the drug.

Effects of the leaf decoction of Momordica charantia (bitter melon) on Mitochondrial Membrane Permeability Transition Pore (MMPTP) and fertility in normal male albino rats.

Momordica charantia (M. charantia), a medicinal plant of the family, Cucurbitaceae, is used in treating an array of ailments including diabetes, heamorrhoids, fevers and various cancers. Programmed cell death may be modulated by an intrinsic pathway involving the release of cytochrome C when the mitochondrial membrane permeability transition (MMPTP) pore is opened. Opening of MMPT pore was assayed using the method of Lapidus and Sokolove. The results obtained revealed that there was a dose-dependent and significant increase in the opening of the MMPT pore in rats orally administered the decoction with maximum induction (11-fold increase) at 55mg/100g body weight (bw), although the extent of opening of the pore was reduced at 65mg/100g bw (9-fold increase). An assessment of the blood parameters of animals orally exposed to the decoction showed significant decrease (p<0.05) in lymphocytes and a significant increase (p<0.05) in neutrophils at 55mg/ 100g bw. Moreover, significant increases (p<0.05) in RBC levels at 45 and 65mg/100g bw, were observed. Similarly, PCV and Heamoglobin values were also elevated at 65mg/100g bw while there was a significant reduction (p<0.05) in MCV and MCH values at 45, 55 and 65mg/100g bw. MCHC values were reduced only in animals that received 65mg/ 100g when compared to control animals. Analysis of the spermiogram of the experimental rats showed significant reductions (p<0.05) in sperm motility and sperm cell concentrations for all animals that were orally exposed to the decoction. There was a significant reduction (p<0.05) in percentage viability in animals that received 45mg/100g bw and above. Morphological abnormalities of sperm cells above the proposed percentage range (10%) were also observed in animals that received 45mg/100g bw and above. However, decoction did not show any significant effect on ALT and AST levels but there were significant increases (p<0.05) in a somewhat dose-dependent pattern in ALP and ãGT levels for all groups in comparison to the control group. These findings thus suggest dose-related negative or toxic effects of sub acute (30-day) oral administration of leaf decoction of M. charantia in albino rats and may therefore pose some danger to humans especially in regard to male fertility in individuals who rely on oral administration of the decoction in treating various ailments.

Effects of methanolic and chloroform extracts of leaves of Alstonei boonei on rat liver mitochondrial membrane permeability transition pore.

The effects of methanolic and chloroform extracts of the leaves of Alstonei boonei, a medicinal plant with anti-malarial, anti-inflammatory and analgesic properties, were assessed on liver mitochondrial membrane permeability transition (MMPT) pore were assessed in experimental animals in vitro and in vivo. The results obtained showed that calcium ions induced the opening of MMPT pore significantly (P< 0.05) in rat liver mitochondria, while spermine (0.1mM) inhibited calcium-induced opening of MMPT pore of these mitochondria thus, indicating that the mitochondria were intact, ab initio. The results further revealed the inhibitory effects of different concentrations of the various extracts of leaves of Alstonei boonei (200 microg/ml, 600 microg/ml, 1000 microg/ml, 1400 microg/ml) compared with spermine. Specifically, the data revealed that methanolic and chloroform extracts of leaves of Alstonei boonei reversed calcium-induced opening of MMPT pore in a concentration-dependent manner (26.5%, 27.4%, 56.4%, 69.3%) for methanolic extract of Alstonei boonei and (9.6%, 34.9%, 51.5% and 82.1%) for chloroform extract of Alstonei boonei, respectively. Although, the MMPT pore was not affected by low concentrations of the methanolic extract of Alstonei boonei (200 microg/ml and 600 microg/ml) in the absence of calcium, the extract at higher concentrations (1000 microg/ ml and 1400 microg/ml) induced the opening of the pore in a concentration-dependent manner. Mitochondria isolated from Wistar strain albino rats orally exposed to various doses of the methanolic extract of Alstonei boonei exhibited pore opening in the absence of calcium. In this respect, maximum (112%) induction of pore opening was obtained at 250mg/kg body weight, while minimum (31%) induction of pore opening was obtained at 200mg/kg body weight. Calcium further increased the extent of opening of the MMPT pore in animals previously exposed to methanolic extract of Alstonei boonei. These findings suggest that certain bioactive components of Alstonei boonei may be involved in inhibiting the opening of the MMPT pore in-vitro and in the induction of the opening of the pore at high doses of the extract with the eventual release of cytochrome C which is a prelude to the progression of programmed cell death.

Induction of membrane permeability transition (MPT) pore opening by Buccholzia coriacea (Engl.) seeds in vitro in rat liver mitochondria.

Apoptosis involves a phenomenon termed mitochondrial permeability transition (MPT) which induces permeability of a voltage-dependent pore to solutes of smaller than 1500Da. Induction of MPT pore is beneficial in case of tumour cells while inhibition of the pore is relevant in conditions such as tissue wastage. The effects of methanol extracts of Buccholzia coriacea (MEBC) commonly known as 'wonder kola' on MPT wa s assessed in vitro in normal rats inthe presence and absence of exogenous calcium- the triggering agent. MPT was estimated by the extent of mitochondrial swelling monitored spectrophotometrically as decreases in absorbance at 540nm. The results revealed that in the absence ofexogenous calcium, MPT pore opening was induced by MEBC at 200 microg/ml, 600 microg/ml, 1000 microg/ml and 1400 microg/ml in a concentration-dependent manner by 21.0, 7.6, 4.2, 3.5 folds, although higher concentrations of MEBC reduced pore opening. Pre-incubation of mitochondria with similar concentrations of MEBC for 5 minutes in the absence of calcium induced pore opening by 1.47, 10, 8.7 and 10.1 folds, respectively. Furthermore, mitochondrial membrane treated with MEBC (200 microg/ml, 600 microg/ml, 1000 microg/ml and 1400 microg/ml) in the presence of exogenous calcium induced pore opening by 63.9%, 44.0%, 23.4% and 64.4%, respectively. Oral administration of MEBC at varying doses of 50 - 200mg/kg b.w to rats for 30 days had no significant effects (p>0.05) on MPT pore opening in the absence of calcium when compared to untreated animals. The liver function tests revealed that the activities of alanine and aspartate amino transferases, alkaline phosphatase, and ã-glutammyl transferase were significantly (p>0.05) increased in serum of animals exposed to MEBC compared to control animals. Overall, Buccholzia coriacea induced MPT pore opening in vitro thus suggesting that certain bioactive components in the extract may prove useful in chemotherapy of tumor cells however, these bioactive agents seem to have been completely metabolized in vivo.