Fatty Acid Biosynthesis: an updated review on KAS inhibitors

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 & 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.

In Vitro and In Vivo Approaches for Screening the Potential of Anti Cancer Agents: A Review

Background: Anticancer drug development is a tedious process, requiring several in vitro, in vivo, and clinical studies. To avoid chemical toxicity in animals during an experiment, it is necessary to envisage toxic doses of screened drugs in vivo at different concentrations. Several in vitro and in vivo studies have been reported to discover the management of cancer. Materials and Methods: This study has focused on bringing together a wide range of in vivo and in vitro assay methods, developed to evaluate each hallmark feature of cancer. Result: This review provides elaborated information about target-based and cell-based screening of new anticancer drugs in the molecular targeting period. This would help to incite an alteration from the preclinical screening of pragmatic compound-orientated to target-orientated drug selection. Conclusion: Selection methodologies for finding anticancer activity have importance for tumor-specific agents. In this study, advanced rationalization of the cell-based assay is explored along with broad applications of the cell-based methodologies considering other opportunities also.

Extracting atomic contributions to binding free energy from molecular dynamics simulations with mixed solvents (MDmix)

Background: Mixed solvents MD simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery Method: Mixed solvents MD simulations have proved to be a useful and increasingly accepted technique with several applications in structure-based drug discovery Result: As such, they are hardly transferable to different molecules. Conclusion: To achieve transferable energies, we present here a method for decomposing the molecular binding free energy into accurate atomic contributions and 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.

Structure-Based De Novo Design and Docking Studies of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds as Dipeptidyl Peptidase-4 Inhibitors

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 a DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

vHTS, 3-D Pharmacophore, QSAR and Molecular docking Studies for the Identification of Phyto-derived ATP-Competitive Inhibitors of the BCR-ABL Kinase Domain

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 anti-cancer plants. A docking score of -10 kcalmol­1 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 (possesses 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.

In-silico Screening of Phytoconstituents on Wound Healing Targets-Approaches and Current Status

: Over recent years, there has been tremendous research focused on the effective utilization of natural products in wound management. Natural or herbal products contain several phytoconstituents that may act on various stages in wound healing and thereby provide a multi-targeted approach especially in the treatment of chronic wounds. Currently, attempts have been made to screen the phytoconstituents present in herbs on various targets involved in wound healing. This review includes a systematic evaluation of scientific reports by various groups of researchers on the herbals evaluated for wound management, their phytochemical profiling, pre-clinical studies, and molecular modeling studies. Various wound targets discussed include Interleukin-1, Interleukin-6, Tumor necrosis factor-α (TNF-α), Thymosin beta-4 (Tβ-4) that regulate the early inflammatory stage and the novel T cell immune response cDNA 7(TIRC7) that regulates angiogenesis. Also, neuropeptides P and Y act on the inflammatory, migratory, and proliferation phases, and growth factors like vascular endothelial growth factor family (VEGF) and placental growth factor family (PGF) are involved in angiogenesis, while the role of Fibroblast growth factor in tissue remodeling is discussed. As many of the natural products include polyherbal systems, this approach can help in the judicious selection of a combination of herbs that will act on multiple targets in the wound healing process and provide a multi-factorial approach in wound management.

Edible Medicinal Plants on Facilitating Childbirth: A Systematic Review

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. 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.

Pharmacological study of A3 Adenosine receptor agonist (AB Meca) in xenograft lung cancer model in mice through in silico and in vivo approach: Targeting TNF-α

Background: Lung cancer is the leading cause of mortality in India. Adenosine receptor (AR) has emerged as a novel cancer-specific target. A3AR levels are upregulated in various tumor cells, which may mean that the specific AR may act as a biological marker and target specific ligands leading to cell growth inhibition. Aim: Our aim was to study the utility of the TNF-α agonist, AB MECA, by in silico (molecular docking) and in vitro (human cancer cells in xenografted mice) studies. Method: Molecular docking on the AB-meca and TNF-α was performed using AutoDock. A549 Human lung cancer 2 ×106 cells per microliter per mouse injected via intrabronchial route. Rat TNF-α level was assessed by ELISA method. Results: AB Meca's predicted binding energy (beng) with TNF-α was 97.13 kcal/mol, and the compatible docking result of a small molecular inhibitor with TNF-α native ligand beng was 85.76 kcal/mol. In vivo, a single dose of lung cancer cell A549 is being researched to potentiate tumor development. Doxorubicin and A3AR agonist therapies have lowered TNF-alpha levels that were associated with in silico function. The A3AR Agonist myeloprotective effect was also found in groups treated with doxorubicin. Conclusion: AB MECA’s higher binding energy (beng) with TNF-α mediated reduction of tumor growth in our lung cancer in vivo model suggests that it may be an effective therapy for lung cancer.

Evaluation of the Antidepressant-like Effect of Total Sterols Fraction and Stigmasterol Isolated from Leaves of Aegle marmelos and Possible Mechanism(s) of Action Involved

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 co-administration 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.

Inebilizumab-cdon: USFDA approval for the treatment of NMOSD (neuromyelitis optica spectrum disorder)

: Inebilizumab-cdon (Uplizna™) was currently approved by the United States Food and Drug Administration (USFDA) for the treatment of NMOSD (neuromyelitis optica spectrum disorder). It was developed by Viela Bio (Nasdaq: VIE) USA. Inebilizumab-cdon (formerly MEDI-551) is a humanized antibody, which induces CD19 + B cell depletion by increasing antibody-dependent cell cytotoxicity (ADCC) and cell phagocytosis (ADCP) of effector cells. Various clinical trials exhibit its safe and effective pharmacokinetic and pharmacodynamic profile. In June 2019, Viela Bio submitted Biologics License Application (BLA) to the FDA based on the findings obtained from the N-Momentum trial. This article summarizes the milestones in the development of Inebilizumab-cdon leading to approval for the treatment of advanced NMOSD.