DCAF1 has been identified as a putative antiviral host target as well as a potential target to enable the proteasome-mediated degradation of therapeutic targets. It has a complex domain architecture, which contains a WD40 repeat (WDR) domain. The WDR domain is one of the most abundant protein-protein interactions (PPIs) domains in the human proteome. Given the significant role that PPIs play in many cellular processes and diseases there has been renewed interest in exploring WDR domain proteins, including DCAF1. Acting through the WDR domain, DCAF1 recruits substrate proteins to the CUL4A-RBX1-DDB1-DCAF1 E3 ubiquitin ligase complex for subsequent proteasomal degradation, which is the key process we aimed to modulate or exploit using small molecule probes. To discover novel DCAF1 probes, the interaction profiles of approximately 3 million commercially available compounds with ~8,500 proteins, including DCAF1, were rapidly predicted using Cyclica’s MatchMaker technology. Briefly, MatchMaker is a deep learning approach capable of assessing small molecule-protein interactions across the proteome. MatchMaker predictions informed the nomination of compounds based not only on predicted binding for DCAF1, but also on the lack of interaction with undesirable off-targets. Using MatchMaker predictions, alongside traditional CADD tools, we predicted and tested experimentally multiple hits for DCAF1, one of which, CYCA-117-70 was subsequently co-crystallized and deposited as the first co-crystal structure of DCAF1 in the PDB [PDB ID: 7SSE 3].

Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from − 33 ± 4.86 mV to − 38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.

Eritrea is one of the developing countries where most of their communities are dependent on herbal medicines for the treatment of Infectious disease. However, this malpractice follows incorrect dosage, administration, formulation, frequency and other non-scientific methods with the inevitable negative effect of the practice which makes it inconvenient for the clients who seek treatment. This study was carried out to get a scientific evidence of antimicrobial activity of two selected important herbal plants. Active part from leaves of Sinapis alba and Brassica nigra were extracted by continuous hot extraction (Soxhlet technique), and different concentrations were obtained by ethanol, N-hexane, aqueous and DMSO solvents. Against Microorganisms of (Escherichia Coli and Staphylococcus aureus from bacterial strains and Candida Albicans from fungal strain) were selected for antimicrobial activity of the plants. Then the extracted solutions were diffused to selected standard organisms inoculated in Muller Hinton Agar using well diffusion technique. Ethanol extracts of S. Alba of 2500mg/ml dissolved in DMSO concentration against E. coli have shown a significant activity with inhibition zones of 30mm. This plant in the same concentration also had a considerable effect against S. aureus and C. Albcaians with a prompting result of 28mm and 25mm zones of inhibition respectively which is greater than the positive control. Moreover, this plant showed almost an equal activity at 1000mg and 250mg which are 20mm and 13mm respectively for C. Albicans, 26mm and 23mm for S. aureus and for E. coli 25mm and17mm. N-hexane extracts of the same plant also showed a remarkable activity at concentrations of 1000mg, 250mg and 50mg, where the zones of inhibition against S. aureus were 18mm, 20mm and 25mm respectively. Ethanol-extract of this plant diluted in ethanol also showed activity at the lowest concentration. Generally, both plants extracted using N-hexane and Ethanol extracts show a remarkable activity against all the selected micro-organisms.

Tumor is one of the most wide-spread diseases across the planet, and along with this - the first in a row of the working-age population death causes. The pathogenesis of uncontrolled tissue growth and malignancy is still unexplored, making the tumor one of the most difficult, if not curable, diseases to treat. Tumor treatment today is carried out by extremely undesirable methods, the leading role among which belongs to chemo- and radiation therapy, the result of which is always inevitable - death. In this regard, there is an urgent need to find medicines that can save the lives hundreds of thousands of people without causing tangible harm to the body. Such drugs can be liposomes, which have long attracted the attention of scientists in the framework of the neoplasia treatment, but still remain at the research stage due to the high cost and complexity of industrial production. Using the data accumulated to date on liposomes and their invasiveness in tumor tissue, we propose our own version of liposome production, which, due to its relatively low toxicity and ease of manufacture, has more chances of being introduced into widespread medical practice: these are liposomes based on the liquid phase from Chaga fungus and the lipid phase with natural peptides relatively easily extracted from plants and microorganisms.

Discovery of new and specific enzyme inhibitor drugs is the growing problem in Pharmaceutical industry and the Research and there is a huge increase in billions of dollars for the development costs for new Chemotherapeutic and Highly potent new drug compounds that specifically target a certain enzyme, receptor or a protein. Recently, Computational Chemistry and Receptor based in silico drug design and discovery is becoming popular among Researchers because the developed methods help with saving time and money by reducing the costs of compounds to be synthesized for the discovery of new drug molecules. In this study, a new drug molecule discovered and computationally predicted to be highly enzyme inhibitor and possibly a potent anti-oxidant and/or anti-cancer drug compound, namely Prondicic Acid ( 2-Oxetanon-3,4-Diacetic Acid or Beta Propiolactone Diacetic Acid ) will be introduced. In addition , the computational methods for the possible activities for the derivatives of these compounds, predicted H-NMR and C-NMR datas and a possible Synthetic route to obtain the compound Prondicic Acid , and reaction mechanisms to possible modify the functional groups that could be synthetically attached to the compound’s Carboxyl groups for derivatization of other Prondicic Acid will be defined.

The aim of this study was to identify and isolate potential biologically active compounds from the stems of Hypoestes aristata (Vahl) Sol. ex Roem. & Schult (Acanthaceae) and test them for their biological activities. The identification and isolation of potential bioactive compounds was achieved through chromatographic techniques such as column chromatography, preparative thin layer chromatography (PTLC), preparative high pressure liquid chromatography (Prep-HPLC), liquid chromatography-solid phase extraction-mass spectrometry (LC-SPE-MS), and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS). The characterisation and structural elucidation of the isolated compounds was mainly facilitated by spectroscopic/spectrometric techniques including 1D NMR (1HNMR, 13C-NMR, dept-135) and 2D NMR (COSY, HSQC, HMBC, NOESY) and high-resolution mass spectrometry (HRMS). From the stems of Hypoestes arisata, ten compounds that belong to the class of lignans were isolated and characterised. Among these compounds, four known butyrolactone lignans hinokinin, savinin, and cubebins; three new butyrolactone lignans (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7- acetoxy-7’-hydroxyhinokinin, and (7S,8S,7’S,8’R)-7,7’-diacetoxyhinokinin; and three new butyrolactol lignans. (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin, 7,7’-diacetoxy-β-cubebin, and (7S,8R,9S,7’R,8’R)-7,7’-diacetoxycubebin) were isolated. The absolute configurations of novel compounds were determined from their electronic circular dichroism (ECD) spectra and by derivatisation into (S) and (R)-MTPA esters. The newly isolated compounds are novel compounds. To the best of our knowledge, this is the first research which has isolated these compounds and confirms their absolute configurations from H. aristata. The compounds were screened for inhibition of a HIV-1 protease enzyme, hinokinin, (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7,7’- diacetoxyhinokinin, and (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin showed moderate protease inhibition at concentrations below 60 µM and other compounds showed insignificant inhibitory activities at concentrations above 100 µM. Additionally, the compounds (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7,7’-diacetoxyhinokinin, and (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin were also tested for cytotoxicity against the MCF-7 and MDA-MB-231 cancer cell lines and found to be inactive at concentrations below 90 µM

Mangifera indica (MI), has been an important medicinal herb for over 4000 years. This genus Mangifera comprises about 30 species of fruiting trees of family Anacardiaceae. Mangifera was widely used in traditional medicine for therapeutic purposes by several cultures. Various parts of Mangifera tree were utilised for the treatment of a variety of ailments. Mangifera indica leaves extract grown in Egypt was subjected to successive chromatography techniques resulted in isolation of a novel non-reported xanthone derivative (TM-1). The in-vitro ability of TM-1 to inhibit elastase and tyrosinase enzymes activities was assessed. The novel compound exhibited remarkable anti-elastase and anti-tyrosinase inhibitory effects with IC50 values of 1.064 µg/mL and 1.336 µg /mL respectively compared to the positive controls. In order to assess the drugability and formulation consideration of TM-1, in silico, ADMET prediction was conducted using the SwissADME server. This included Lipinski’s rule of five, such as lipophilicity, solubility, and Pharmacokinetic properties as GIT absorption, distribution, metabolism, and skin permeation. All the physicochemical properties of TM-1 are within desirable ranges except for high polarity which may be attributed to the presence of the sugar moiety.TM-1 showed promising predicted topological aqueous solubility and reasonably predicted skin penetration suggesting the suitability of TM-1 for topical formulation. This is coherent with the in-vitro Antiaging evaluation.

γ-Secretase (GS) is a key target for the potential treatment of Alzheimer’s disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (S)-3 (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in-vitro and in-vivo DMPK profile. Furthermore, based on its in-vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g. GLP toxicology and scale up activities). Furthermore, we will present a novel saturated phenyl bioisostere used in this compound design and compare its properties versus the now more standard BCP and related derivatives.

The most common genetic causes of Parkinson’s Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. Increased Leucine Rich Repeat protein Kinase 2 (LRRK2) activity is hypothesized to cause PD in those who inherit GS-LRRK2, as well as other less common LRRK2 mutations, and possibly even contribute to the pathogenesis of sporadic PD in people without LRRK2 mutations. The clear advantage of these non-selective LRRK2 kinase inhibitors is their possible indication for all forms of PD. Unfortunately, multiple advanced compounds of this type of LRRK2 kinase inhibitor are accompanied by concerning untoward effects in lung and kidney (e.g., compounds developed by Genentech and Merck, GNE-7915 and MLi-2, respectively), calling into question the suitability of relatively non-selective LRRK2 kinase inhibitors for long-term treatment of older individuals. Furthermore, although these side-effects in lung and kidney have been reported to be reversible, the safety of long-term administration of such compounds is untested. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp=0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.