Current Drug Discovery Technologies - Volume 19, Issue 2, 2022

Since the early twentieth century, with the isolation of penicillin and streptomycin in the 1940s, the modern era of anti-infective drug development has gained momentum. Due to the enormous success of early drug discovery, many infectious diseases were successfully prevented and eradicated. However, this initial hope was wrongheaded, and pathogens evolved as a significant threat to human health. Drug resistance develops as a result of natural selection’s relentless pressure, necessitating the identification of new drug targets and the creation of chemotherapeutics that bypass existing drug resistance mechanisms. Fatty acid biosynthesis (FAS) is a crucial metabolic mechanism for bacteria during their growth and development. Several crucial enzymes involved in this biosynthetic pathway have been identified as potential targets for new antibacterial agents. In Escherichia coli (E. coli), this pathway has been extensively investigated. The present review focuses on progress in the development of Kas A, Kas B, and Fab H inhibitors as mono-therapeutic antibiotics.

Background: Despite advances and the availability of newer drugs to facilitate childbirth, the interest in using natural treatments is on the rise. More than 20 percent of pregnancies require induction of labor, which is associated with side effects and increased risk of cesarean surgery. For this reason, the use of medicinal plants is considered healthier. Objective: The present study is a systematic review of the role of oral herbs in facilitating childbirth. Method: This review was conducted via searching the Medline/PubMed, Google Scholar, Scopus, and SID databases. The review began systematically and with no time constraints. It lasted until December 29, 2020. Results: Twenty clinical trials investigated the impact of edible plants on increasing cervical readiness, stimulating labor onset, reducing pain intensity, and shortening the duration of labor. Five studies have revealed the positive impact of saffron. Two studies reported the same effect by chamomile. Three studies showed the positive impact of boiled dill seeds, and two studies showed the impact of date and date syrup. Another study reported the impact of Descurainia Sophia, and six studies also showed the positive effect of castor oil on uterine stimulation, strengthening and relieving labor pains, which eventually lead to facilitating labor. One study also showed no improvement in bishop score after consumption of primrose capsules. Conclusion: The positive effect of edible medicinal plants on facilitating childbirth has been shown in the mentioned studies. However, more studies with a larger sample size are needed, and there is also a need for a more detailed study of the possible mechanisms of plant effects.

Background: Aegle marmelos Corr. (Rutaceae) commonly known as ‘Indian Bael’ has been used as a brain tonic traditionally. However, despite this traditional use, not enough scientific report is present that can confirm the use of this plant in neurological disorders. Thus, the total sterols fraction and stigmasterol from the leaves of Aegle marmelos were investigated for antidepressant-like effect along with their possible mechanism(s) of action by primarily performing acute toxicity study of total sterols. Methods: An acute toxicological study was carried out at a single oral dose of 2000 mg/kg. Sign of toxicity was observed by estimating biochemical and performing histopathological analysis. For the antidepressant-like effect, different doses of total sterols (50-200 mg/kg, p.o. for seven days) and stigmasterol (5- 20 mg/kg, i.p. acute) were administered in mice using TST and FST models. To evaluate the mechanism of action, mice were pretreated with GABA, 5-HT, DA, adrenergic antagonists, and glutamate agonists. Furthermore, a neurochemical study was performed following TST and molecular docking study was also performed to determine the binding affinity of stigmasterol. Results: Total sterols fraction presents no sign of toxicity up to the oral dose of 2000 mg/kg. Oral treatment of total sterols and acute intraperitoneal treatment of stigmasterol (except 5 mg/kg) reduced the immobility time significantly. Pretreatment with pCPA (5-HT synthesis inhibitor) and NMDA (an agonist of the glutamate site) effectively reversed the immobility time of total sterols and stigmasterol (except pCPA) in TST. However, bicuculline (competitive GABA antagonist), haloperidol (D2 dopaminergic antagonist) and prazosin (α1 adrenergic antagonist) could not reverse the immobility time. Meanwhile, total sterols also effectively altered the hippocampus 5-HT and Glu levels. Also, the result of the molecular docking study depicted that stigmasterol has an affinity to the NMDA receptor. Conclusions: The present study suggests that the total sterols fraction did not produce any acute toxicity in rats. Also, we reported that total sterols, stigmasterol and sub-effective stigmasterol coadministration with fluoxetine significantly reduced the time of immobility in TST and FST confirmed the antidepressant-like effect of total sterols fraction and stigmasterol. Moreover, further findings suggest that the antidepressant-like effect of total sterols might be mediated by the serotonergic and glutamatergic systems. Whereas only the glutamatergic system was involved in the antidepressant activity of stigmasterol.

Background: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics. Objective: Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski’s rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach. Methods: Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software. Results: 5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski’s rule of five. Compounds were found to have good ADME profile and low toxicity predictions. Conclusion: Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

Background: Chronic myelogenous leukaemia (CML) constitutes about 15 % of adult leukaemia and is characterized by the overproduction of immature myeloid cells. Methods: In this study, a virtual high throughput screening (vHTS) technique was employed to screen a library of phytochemicals of reported plants having anticancer activity. A docking score of -10 kcalmol^-1 was used as the cut-off for the selection of phyto-compounds for pharmacophore-based virtual screening. Statistically robust and thoroughly validated QSAR model (R = 0.914, R² = 0.836, Adjusted R² = 0.764, LOO-CV= 0.6680) was derived for the inhibition of BCR-ABL kinase domain. Results: The virtual screening, pharmacophore screening, QSAR model and molecular docking techniques applied herein revealed ellagic acid, a polyphenolic compound, as a potential competitive inhibitor of the BCR-ABL kinase domain. Ellagic acid binds to the inactive ABL state and forms similar interactions with key residues within the BCR-ABL Kinase domain as obtained in ponatinib (having inhibitory effects on the ABL thr-315I mutant). It forms hydrogen bond interaction with thr-315 residue (the gatekeeper residue). It is not likely to be prone to the various mutations associated with nilotinib because of its small size. Conclusion: The procedure of VHTs, Pharmacophore, QSAR, and molecular docking applied in this study could help in detecting more anti-CML compounds.

Background: Mixed solvents MD (MDmix) simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery. One of the assumptions behind the methodology is the transferability of free energy values from the simulated cosolvent molecules to larger drug-like molecules. However, the binding free energy maps (ΔGbind) calculated for the different moieties of the cosolvent molecules (e.g. a hydroxyl map for the ethanol) are largely influenced by the rest of the solvent molecule and do not reflect the intrinsic affinity of the moiety in question. As such, they are hardly transferable to different molecules. Method: To achieve transferable energies, we present here a method for decomposing the molecular binding free energy into accurate atomic contributions. Result: We demonstrate with two qualitative visual examples how the corrected energy maps better match known binding hotspots and how they can reveal hidden hotspots with actual drug design potential. Conclusion: Atomic decomposition of binding free energies derived from MDmix simulations provides transferable and quantitative binding free energy maps.

Background:Garcinia mangostana, commonly also called mangosteen, is an evergreen tropical tree, and its pericarps have been used in traditional herbal medicine for different diseases. The anticancer efficacy of the ethanolic extract from the pericarps of Garcinia mangostana was investigated in human prostate cancer cells (PC3), melanoma cells (B16F10), breast cancer cells (MCF7), and glioblastoma (U87) cell lines. Methods: 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was used to measure cell viability. Propidium iodide (PI) staining and analysis on a flow cytometer were used to identify apoptosis. Action on cell migration was evaluated by scratch assay and gelatin zymography. Furthermore, the level of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity was measured. Moreover, we investigated the synergistic efficacy with several combinations of Garcinia mangostana extract (GME) with doxorubicin. Results: GME reduced cell viability in malignant cell dose time-dependently. GME-induced sub- G1 peak in flow cytometry histogram of treated cells control representing apoptotic cell death is involved in GME toxicity. Furthermore, GME exhibited inhibitory effects on the migration ability of U87 cells, which was accompanied by inhibition in the activity and expression of MMP2 (matrix metalloproteinase-2). Besides, GSH level and SOD activity were significantly reduced while there was an increase in ROS and MDA concentration following 24 hr of GME treatment. Moreover, a combination of GME (1.5–25 μg/mL) with Dox (6 μg/mL) displayed synergistic efficacy and cell growth inhibition. Conclusion: In conclusion, GME could cause cell death in PC3, MCF7, U87, and B16F10 cell lines, in which apoptosis plays an imperative role. Plant extract decreased the migration ability of the cells by inhibiting the activity and expression of Matrix metalloproteinases (MMPs). G. mangostana could be a promising therapeutic strategy to treat cancer in the future.