Discovery of potential epidermal growth factor receptor inhibitors from black pepper for the treatment of lung cancer: an in-silico approach.

A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is one of the main tumour markers in many cancer types and also plays a crucial role in cell proliferation, differentiation, angiogenesis, and apoptosis, which is a result of the auto-phosphorylations (kinase activity enhancement) that trigger signals involved in different cellular processes. Due to the discovery that non-small cell lung cancer (NSCLC) is a cause of this kinase activity enhancement, so far, several inhibitors have been tested against EGFR, but the side effects of these inhibitors necessitate an urgent measure to come up with an inhibitor that will be more specific to the cancer cells and not affect self-cells. This study was conducted to evaluate the efficacy of 37 compounds derived from Piper nigrum against EGFR using computer-aided drug design. Based on molecular docking, induced-fit docking, calculation of free binding energy, pharmacokinetics, QSAR prediction, and MD simulation. We propose five (5) lead compounds (clarkinol A, isodihydrofutoquinol B, Burchellin, kadsurin B, and lancifolin C) as a novel inhibitor, with clarkinol A demonstrating the highest binding affinity (-7.304 kcal/mol) with EGFR when compared with the standard drug (erlotinib). They also showed significant moderation for parameters investigated for a good pharmacokinetic profile, with a reliable R2 coefficient value predicted using QSAR models. The MD simulation of clarkinol A was found to be stable within the EGFR binding pocket throughout the 75 ns simulation run time. The findings showed that clarkinol A derived from Piper nigrum is worth further investigation and consideration as a possible EGFR inhibitor for the treatment of lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00197-1.

Effect of Chrysophyllum albidum fruit pulp powder on antioxidant and proinflammatory genes in non-diabetic and type 2 diabetic rats.

BACKGROUND: Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia resulting from insulin deficiency or dysfunction. The imbalance between free radicals and antioxidants known as oxidative stress has been implicated in the pathogenesis and complications associated with DM. Chrysophyllum albidum is a seasonal fruit found to be rich in natural antioxidants. METHODS: DM was induced by high-fat diet dietary supplementation for 14 days followed by intraperitoneal injection of streptozotocin (35 mg/kg). Thirty-five experimental rats were then divided into seven groups viz.: non-diabetic control; diabetic control; metformin; diabetic and non-diabetic fed with 5 and 10% C. albidum fruit pulp powder (CAFPP). Fasting blood glucose was done with an automatic auto-analyzer and weights were monitored at three-day intervals. The expressions of Nrf2, SOD, CAT, GST, TNF-α, DPP4, and insulin were investigated using RT-PCR. Schrödinger suites was used for docking of C. albidum phytocompounds with insulin. RESULTS: Diabetic rats fed with CAFPP for thirteen days have their blood glucose lowered significantly (p < 0.05) and gained weight compared to diabetic control. CAFPP significantly (p < 0.05) up-regulated Nrf2, CAT, GST, SOD, and insulin genes expression in the diabetic group relative to diabetic control with concomitant down-regulation of TNF-α and DPP4 genes expression. Molecular docking of compounds previously characterized from C. albidum revealed that they are potent ligands of insulin receptors. CONCLUSION: The study revealed that CAFPP could be effective in the management of DM-related oxidative stress by up-regulating antioxidant and down-regulating pro-inflammatory genes expression. It also positively modulates genes associated with glucose metabolism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00921-0.

Discovery of Traditional Chinese Medicine Derived Compounds as Wild Type and Mutant Plasmodium falciparum Dihydrofolate Reductase Inhibitors: Induced Fit Docking and ADME Studies.

BACKGROUND: In a bid to come up with effective compounds as inhibitors for antimalarial treatment, we built a library of 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Database@Taiwan. METHODS: The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolatereductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to offer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition. RESULTS: We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking scores with both the wild type and mutant pfDHFR. They were further subjected to Induce Fit Docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the compounds were also considered. The inhibition profile of the compounds revealed that a number of compounds formed intermolecular interactions with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Most of the compounds can be considered as drug candidates due to their antiprotozoal activities and accordance with the Lipinski's Rule of Five (ROF). CONCLUSION: The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2.

SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2. Papain-like protease (PLpro) of the viral polyproteins is essential for maturation and infectivity of the virus, making it one of the prime targets explored for SARS-CoV-2 drug design. This study was conducted to evaluate the efficacy of ~ 50,000 natural compounds retrieved from IBS database against COVID-19 PLpro using computer-aided drug design. Based on molecular dock scores, molecular interaction with active catalytic residues and molecular dynamics (MD) simulations studies, STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido) propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro. It demonstrated favourable docking score, the free energy of binding, interacted with key amino acid residues necessary for PLpro inhibition and also showed significant moderation for parameters investigated for ADME/tox (Adsorption, distribution, metabolism, excretion and toxicological) properties. The edge of the compound was further established by its stability in MD simulation conducted for 30 ns employing GROMACS software. We propose that STOCK1N-69160 is worth further investigation for preventing SARS-CoV-2.

Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies.

Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins.