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Brain Targeted Drug Delivery Systems
Published in Ambikanandan Misra, Aliasgar Shahiwala, In-Vitro and In-Vivo Tools in Drug Delivery Research for Optimum Clinical Outcomes, 2018
Manisha Lalan, Rohan Lalani, Vivek Patel, Ambikanandan Misra
The large virtual libraries of chemicals are screened using several models that have been developed based on the molecular descriptors or the fingerprints. The models have been designed based on certain general rules. The rule of thumb that has been evaluated and agreed upon by a number of researchers is that if the sum of nitrogen and oxygen (N + O) atoms in a molecule is five or less, the log P – (N + O) > 0, polar surface area (PSA) is below 90 Å2, and the molecular weight is below 450, the compound is expected to show BBB permeability. High-throughput methods may be based on molecular docking or descriptor-based strategies. Molecular descriptor-based strategies have given less false negative outcomes, but more false positive outcomes, as these models don’t account for the effect of transporters. The molecular docking technique determines the P-glycoprotein substrates or inhibitors dealing with the phenomenon of active multidrug efflux by P-gp in the brain (Mensch et al. 2009; Norinder and Haeberlein 2002; Kelder et al. 1999).
Dendrimer Space Concept: A Futuristic Vision in Nanomedicine to Develop New Drugs
Published in Anne-Marie Caminade, Cédric-Olivier Turrin, Jean-Pierre Majoral, Phosphorus Dendrimers in Biology and Nanomedicine, 2018
Serge Mignani, Jean-Pierre Majoral
Importantly, today, traditional Lipinski’s criteria/guidelines (called rule of 5, Ro5) are widely used by the medicinal chemistry community to predict not only the oral absorption of compounds, but also overall drug-likeness [10]. Additional parameters determining favorable oral bioavailability are as follows: fully rotatable bonds <5 and polar surface area (PsA) <140A2 (blood-brain barrier penetration: <80A2) [11]. Ro5 provides suitable information about absorption or permeation, thus helping to reduce the attrition rate at later pre-market stages.
Nano-QSAR for Environmental Hazard Assessment: Turning Challenges into Opportunities
Published in Agnieszka Gajewicz, Tomasz Puzyn, Computational Nanotoxicology, 2019
Willie Peijnenburg, Guangchao Chen, Vijver Martina
On the other hand, other than the general consensus taking ion release and ROS generation as driving factors in nanotoxicity, it is evident that other mechanisms of toxicity also play a vital role in certain cases. Xiao et al. [62] reported that for both Cu and ZnO ENMs, the particles per se, rather than the dissolved ions, provided the major contribution to the toxicity to Daphnia magna (26% and 31%, respectively). Similarly, Hua et al. [108] also revealed a dominant contribution of ZnO ENMs over the Zn ion tested for zebrafish embryos, for which the dissolution-driven mechanism of ENM toxicity apparently does not apply. More precisely, it was shown that the shape of ENMs significantly affect ENMs’ toxicity as needle-shaped ZnO ENMs were proven to be the most toxic to Phaeodactylum tricornutum as compared to morphologically different ENMs with equal solubility and ion release [145]. Observations of nanotoxicity affected by the shape of ENMs were also reported for ZnO nanospheres, nanosticks, and cuboidal submicron particles [108]. Computational studies proved the involvement of surface property-related descriptors in nano-QSAR modeling, such as the surface area and coating [83, 90, 116, 121], hydrophobicity and polar surface area of surface molecules [3, 89], surface-area-to-volume ratio [121], zeta potential [120], and the Wigner-Seitz radius of an oxide’s molecule (which describes the available fraction of molecules on the surface of ENMs) [91, 121]. The Wigner-Seitz radius also relates to MW and density and, therefore, also to the molecular volume. All of them have been included in the models [3, 89, 119, 121]. Descriptors related to size [3, 29, 88–90, 117, 119, 120], material composition [29, 83, 90, 119, 121], and aggregation behavior [91, 119–121] were also found to affect nanotoxicity.
Comprehensive biological evaluation (DNA-binding, cleavage, and antimicrobial activity) of β-diketimine Schiff base ligands and their Cu(II) and Zn(II) complexes
Published in Journal of Coordination Chemistry, 2021
The pharmacokinetic activities of the synthesized compounds were scrutinized by SWISS ADME online software, which is displayed in Table 6. Using five Lipinski’ rules, these results can be assessed [40]. The log(p) value for all the compounds is less than 5 and the nitro-substituted compounds have more ability to enter into the genetic membrane (because of its value lower than 5). Total Polar Surface Area (TPSA) represents the surface sum over all of the polar oxygen and nitrogen atoms (including their attached hydrogen atom). The optimized TPSA values are less than 140 Å for the efficient transfer of the synthesized compounds inside the intestine and BBB. Table 6 clearly shows that all the compounds have TPSA values below 140 Å (from 63.52 to 125.16 Å), which reveals the lead like activity. Moreover, according to Veber’s rule, the active oral mode of administration requires the number of hydrogen bond donors, acceptors and the rotatable bonds should be lower than 5, 10, and 10, respectively [41]. This table implies that all the compounds have satisfied the necessary condition for the oral activity, good absorbance inside the GIT (GastroIntestinal Tract) and crossed the BBB (Blood Brain Barrier). The bioavailability score for all the ligands is greater than zero (0.55), which implies that they are biologically active [42].
Non-targeted GC/MS analysis of exhaled breath samples: Exploring human biomarkers of exogenous exposure and endogenous response from professional firefighting activity
Published in Journal of Toxicology and Environmental Health, Part A, 2019
M. Ariel Geer Wallace, Joachim D. Pleil, Karen D. Oliver, Donald A. Whitaker, Sibel Mentese, Kenneth W. Fent, Gavin P. Horn
Chromatography data were modeled using Advanced Chemistry Development, Inc (ACD)/Labs software ACD/ChromGenius (Toronto, Ontario, Canada) to predict RT for candidate compounds assigned as features. The model was developed by dividing compounds from the standards with known RT into a training set of 34 chemicals (~80%) and a test set of 8 chemicals (~20%) (Table S1). These chemicals originated from either the Linde TO-14 A 43 component mix or the Restek PAH standard and were previously analyzed using the same column and chromatographic conditions as employed in the current method. In the similarity search options tab, the dice coefficient was selected to show the best 25 records. The equation was correlated linearly with 4 points per parameter and 0.01 delta error for the new parameter in the equation. The equation was set to not be utilized if the error was >0.9. The following GC parameters were used for modeling: boiling point, octanol-water partitioning coefficient of the molecule (logP), polar surface area, molecule volume, molecule weight, molar refractivity, H donors, and H acceptors.
The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation
Published in Journal of Environmental Science and Health, Part A, 2020
Doaa A. Abdelrheem, Shimaa A. Ahmed, H. R. Abd El-Mageed, Hussein S. Mohamed, Aziz A. Rahman, Khaled N. M. Elsayed, Sayed A. Ahmed
Lipinski’s rule of five is commonly utilized in development and drug design to expect oral bioavailability of drug molecules. Lipinski’s rule was established based on five rules to compute the ability of the compound to act as an orally active drug was calculated and shown in Table 6. So, orally active drugs must have no more than one violation of the following standards: (i) octanol/water partition coefficient (log P) which measured the lipophilicity of a molecule must be not greater than five. (ii) A molecular weight (MW) less than 500 Da. (iii) not more than five hydrogen bond donors (nON). (iv) not more than 10 hydrogen bond acceptors (nOHN). The topological polar surface area (TPSA) is measured the bioavailability of the drug molecule. TPSA is closely related to the hydrogen bonding potential of a compound. TPSA of studied compounds was noticed in the range of 25.87–153.50 Å and is well below the limit of 160 Å. It can be predicted that all studied bioactive compounds obeyed Lipinski’s rule of five and are likely to be orally active except compounds 5 and 9 as shown in Table 6. The database supports ADMET profiles which involve some features to study the ability of the studied compounds to act as drug leads such as Blood–brain barrier (BBB) penetration, human intestinal absorption (HIA), Caco-2 cell permeability, CYP inhibitory promiscuity, AMES toxicity, carcinogenicity, and rat acute toxicity LD50 are calculated and displayed in Table 7. As shown in Table 6, all studied compounds may cross blood brain barrier (BBB) and absorb in the human intestine (HIA) along are permeable for Cacoe2 cells, whereas, compound 5 showed a negative result for BBB, HIA, and Cacoe2 cell permeability. Cytochrome P450 (CYP) is a group of isozymes containing the metabolism of drugs, steroids, fatty acids, bile acids, and carcinogens. The results indicate that these studied compounds are non-substrate and non-inhibitor of CYP enzymes.[13,60] In terms of AMES toxicity, all studied compounds were observed to be non-toxic. Carcinogenicity model indicated non-Carcinogenic nature of all studied compounds. Rat Acute Toxicity LD50 of all studied compounds was found between 1.95 and 2.75 mol/kg. The finding strongly provides the ability of most of all studied compounds to act as a drug, except compound 5 as shown in Table 7.