STRUCTURE-BASED DESIGN OF NOVEL RILPIVIRINE ANALOGUES AS HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS THROUGH QSPR AND MOLECULAR DOCKING

Objectives: The aim of this research is to investigate the better biological activities from Rilpivirine analogues based on their Quantitative Structure-Property Relationship (QSPR) and pharmacophore study.Methods: In this study, we had designed six Rilpivirine analogues. The complementary aided-computational drug design and molecular docking was employed to find the best lead candidate. The drug-likeness properties of Rilpivirine analogues were defined by following the Rule of Five.Results: The drug-likeness properties of Rilpivirine derivatives (RVN 1-6) were defined by the Rule of Five (RO5), which RVN3 compound showed the best RO5 score among others. However, the log P value of RVN1 and RVN4 are lower than 5, while RVN2, RVN3, RVN5 and RVN6 have log P values greater than 5. Based on the solubility, RVN1 and RVN4 compounds are more soluble than other analogues including Rilpivirine prototype (RVN). The topological polar surface area (TPSA) score of RVN1 and RVN4 showed greater scores compared to others. On the other hand, the TPSA score of all Rilpivirine analogues are below 140 Ã…2. The absorption, distribution, metabolism, and excretion (ADME) properties of Rilpivirine analogues were determined, according to blood brain barrier penetration were found within the range of-1.2 to-2.2, which RVN4 showed the lowest value compared to others, while RVN showed the highest value. The percentage of human intestinal absorption was observed 100% to all compounds. The plasma protein binding percentages was obtained within the range 99.03-99.57%. Moreover, the hydrogen bond donor contribution of all compounds was in the range 2-4 bonds, while the acceptor hydrogen bond was found 6 bonds from all compounds. The mutagenicity properties showed all compounds could cause mutagenic effect in long-term administration. The carcinogenicity tests were done in mouse showed positive results to all compounds, while carcinogenicity test in rat showed negative results upon all compound, except RVN3 which gave positive result. From molecular docking result, RVN 1 and RVN 4 showed higher potential inhibition activities to Reverse Transcriptase Human Immunodeficiency Virus Type 1 (HIV-1 RT) compared other analogues.Conclusion: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a great potential inhibition against HIV-1 RT. From high throughput computational approach, we suggested that RVN 1 and RVN 4 are the potential drug candidates which have better activity among other Rilpivirine derivatives

Evaluasi Sensori, Nilai Gizi, Dan Sifat Fisik Cookies Kedelai Hitam Untuk Ibu Menyusui

The purpose of this study was to get sensory attributes and determine the nutrient composition and physical property of black soybean cookies for breastfeeding mothers. Cookies were made from 5 ratio variations of wheat flour : black soybean flour with baking temperature 1350C for 30 minutes. Further analysis of sensory (taste, flavor, color, texture, aftertaste, and overall; physical property (hardness); and chemical analysis (moisture, protein, lipid, ash, and carbohydrate) to determine the nutritional composition. The results showed that the cookies with ratio wheat flour : black soybean 75:25 was the most preferred cookies by panelists. One cookies contained 3.17 grams of carbohydrate; 0.62 grams of protei; and 1.62 grams of lipid. It could suffice 1.12% of total energy based on Recommended Dietary Allowance of breastfeeding mother per day. The level of hardness was 21.90 N, higher than the control cookies without black soybean flour

In Silico Screening and Designing Synthesis of Cinchona Alkaloids Derivatives as Potential Anticancer

P-glycoprotein (P-gp) resistance in cancer cells decreases intracellular accumulation of various anticancer drugs. This multidrug resistance (MDR) protein can be modulated by a number of non-cytotoxic drugs. We have screened 30 chincona alkaloids derivatives as a potent P-gp inhibitor agent in silico. Hereby, we report the highest potential inhibitions of P-gp is Cinchonidine isobutanoate through molecular docking approach. with affinity energy -8.6 kcal/mol and inhibition constant, Ki is 4.89 x 10-7 M. Cinchonidine isobutanoate is also known has molecular weight below 500, Log P value 3.5, which is indicated violation free of Lipinski`s rule of five. Thus, Cinchonidine isobutanoate is the most potent compound as anticancer compare to other Cinchona alkaloids. Ultimately, we design Cinchonidine isobutanoate for further lead synthesis by using DBSA, act as a combined Brønsted acid-surfactant-catalyst (BASC) to obtain high concentration of organic product by forming micellar aggregates which is very powerful catalytic application in water environment

1H, 13C and 15N Backbone Assignment of the EC-1 Domain of Human E-Cadherin

The final publication is available at Springer via http://dx.doi.org/10.1007/s12104-013-9539-6The EC1 domain of E-cadherin has been shown to be important for cadherin-cadherin homophilic interactions. Cadherins are responsible for calcium-mediated cell-cell adhesion located at the adherens junction of the biological barriers (i.e., intestinal mucosa and the blood-brain barrier (BBB). Cadherin peptides can modulate cadherin interactions to improve drug delivery through the blood-brain barriers (BBB). However, the mechanism of modulating the E-cadherin interactions by cadherin peptides has not been fully elucidated. To provide a basis for subsequent examination of the structure and peptide-binding properties of the EC1 domain of human E-cadherin using solution NMR spectroscopy, the 1H, 13C and 15N backbone resonance of the uniformly labeled-EC1 were assigned and the secondary structure was determined based on the chemical shift values. These resonance assignments are essential for assessing protein-ligand interactions and are reported here

Comparative study of estrogen receptor α, β mRNA expressions of endometriosis and normal endometrium in women and analysis of potential synthetic anti-estrogens in silico

Endometriosis is a multifactorial disease in which genetic and environmental factors interact causing its pathogenesis. The aim of this study was to investigate the expression pattern of estrogen receptor α (ERα) and β (ERβ) in endometriosis patients compared to normal endometrioum (n=18) as a control by using Quantitative Real Time PCR method. Moreover, we also measured serum estradiol levels of endometriosis patients in the proliferation phase of the menstrual cycle using the enzyme-linked immunosorbent assay method. The mRNA expression of ERβ was significantly higher in the endometriosis group compared to control, and the result of t-test showed that were significantly different (P<0.05). Overexpression of ERβ in endometriosis was likely to have other significant important impacts in the pathology of endometriosis that allowed ERβ to stimulate prostaglandin production in endometriosis tissue and cells. Estradiol content did not correlate with the ERα expression, and it is weakly correlated with ERβ mRNA expression. Molecular docking analysis showed that ERα and ERβ have different binding interactions with synthetic antiestrogens, whereas the best inhibitor was Ral2 to ERα and Aco1 to ERβ. Thus, both inhibitors could be used as leads in further investigation of ERα, ERβ inhibitory activities in vitro and in vivo

PyPLIF HIPPOS and Receptor Ensemble Docking Increase the Prediction Accuracy of the Structure-Based Virtual Screening Protocol Targeting Acetylcholinesterase

In this article, the upgrading process of the structure-based virtual screening (SBVS) protocol targeting acetylcholinesterase (AChE) previously published in 2017 is presented. The upgraded version of PyPLIF called PyPLIF HIPPOS and the receptor ensemble docking (RED) method using AutoDock Vina were employed to calculate the ensemble protein–ligand interaction fingerprints (ensPLIF) in a retrospective SBVS campaign targeting AChE. A machine learning technique called recursive partitioning and regression trees (RPART) was then used to optimize the prediction accuracy of the protocol by using the ensPLIF values as the descriptors. The best protocol resulting from this research outperformed the previously published SBVS protocol targeting AChE. © 2022 by the authors