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Modelling and Simulation of Nanosystems for Delivering Drugs to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Tânia F. G. G. Cova, Sandra C.C. Nunes
For example, Winkler and Burden modelled BBB partitioning of more than 100 compounds using the Bayesian regularised neural network (BRNN) [43]. The authors combined three families of molecular descriptors to model the partitioning of several drugs across the BBB. The relative significance of the molecular descriptors for the best-predictive BBB model was estimated and compared with other descriptors from literature models of BBB partitioning. It was shown that BRNN was robust, without a tendency to overfitting, and not strongly affected by poor data (R2 = 0.81 and Q2 = 0.65). The parameters logP and polar surface area (PSA) were identified as relevant in the description.
Central Nervous System Effects of Essential Oil Compounds
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Elaine Elisabetsky, Domingos S. Nunes
Lipinsky's “rule of five” describes a set of requirements for a drug to be orally absorbed (Lipinski et al., 2012): (1) molecular weight, MW <500; (2) polar surface area (Clark, 1999), PSA <140 Å2; (3) octanol/water partition coefficient (Leo, 1993), LogP <5; (4) no more than five hydrogen bond donors (HBD); and (5) no more than 10 hydrogen bond acceptors (HBA). The HBD and HBA values are additives, and in the rule of five, the sum of both types of hydrogen bonding must be equal or less than 10. In this chapter we will use the molecular descriptors TPSA (Clark, 1999) and XLogP3 (Cheng et al., 2007) instead of PSA and LogP, respectively. As can be seen in Table 11.1, the psychoactive volatiles (PAVs) that originated from EOs easily conform to the conditions placed by the rule of five.
Bioavailability of inhaled compounds
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Tronde et al. looked at two slightly different physico chemical properties to predict the absorption of 34 inhaled drugs in the market that they termed “first dimension or t[1]” and a “second dimension or t[2]” (19). The t[1] was related to size (including molecular volume; surface area [polar/nonpolar]; hydrogen bonding donors/acceptors; electronic parameters, including charge and dipoles; and topological parameters, including molecular weight, atom/bond/ring counts, and connectivities), and t[2] was related to lipophilicity (including LogD and LogP). They concluded that the absorption rate correlated better with the molecular polar surface area and the hydrogen bonding potential. However, this conclusion may be viewed with caution because the compounds that they studied mainly included beta 2-agonists and corticosteroids, with a few anesthetics (19).
Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Samar El-Kalyoubi, Samiha A. El-Sebaey, A. M. Rashad, Hanan A. AL-Ghulikah, Mostafa M. Ghorab, Sherin M. Elfeky
Several parameters, including structural, molecular, and physicochemical properties expressed in Lipinski’s rule, should be considered. Lipinski’s rule (rule of five) represents broad and general guidelines for orally bioavailable drug candidates, which include the following parameters: molecular weight (M. wt. ≤ 500 g/mol), number of hydrogen bond acceptors ≤ 5, number of hydrogen bond donors ≤ 10, and partition coefficient (log P) ≤561. Topological polar surface area (TPSA), which is another important physicochemical property that needs to be studied for drug candidates, is used to express the surface associated with polar atoms, ideally TPSA ≤ 16062. Similar to 5-fluorouracil, both compounds 3a and 5d showed no violation of Lipinskìs rule, with molecular weights ranging from 305.19 g/mol to 354.40 g/mol. Furthermore, compounds 3a and 5d had acceptable partition coefficients and topological polar surface areas ranging from −0.61 to 2.09 and 54.86 to 109.98, respectively, whereas log p and TPSA of 5-fluorouracil were −0.73 and 65.72, respectively. Moreover, both compounds had 2 to 4 rotatable bonds, 2 to 3 hydrogen bond acceptors, and 1 to 3 hydrogen bond donors following Lipinskìs rule of five (Table 8).
Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Gaofeng Zhu, Ping Bai, Keren Wang, Jing Mi, Jing Yang, Jiaqi Hu, Yujuan Ban, Ran Xu, Rui Chen, Changning Wang, Lei Tang, Zhipei Sang
The drug-like properties of compounds 5a, 5d, 5e, 5f, and 5h were evaluated using the Molinspiration property program28. A widely accepted method to predict ADME properties is the Rule of Five proposed by Lipinski in 1997. The items of Rule of Five were that octanol-water partition coefficient (log P) <5, molecular weight (MW) <500, number of hydrogen-bond donors (n-OHNH) <5, number of hydrogen-bond acceptors (n-ON) <10, number of rotatable bonds ≤10, and the rotatable bonds were single bonds that are not adjacent to triple bonds, do not connect hydrogen or halogen atoms and are not included in rings containing <5 single bonds. Topological Polar Surface Area (TPSA), for the CNS drugs, TPSA ≤90 Å2. As demonstrated in Table 4, compounds 5a, 5d, 5e, 5f, and 5h complied with the Rule of Five, deserving further investigations.
Biopharmaceutics considerations for direct oral anticoagulants
Published in Drug Development and Industrial Pharmacy, 2021
Rafael Pereira de Andrade, Tamires Guedes Caldeira, Bárbara Vasconcelos Vasques, André Luís Morais Ruela, Jacqueline de Souza
Besides the LogP, the polar surface area (PSA) and molecular weight are parameters that predict the degree of drug absorption in the GI tract. PSA and permeability are inversely proportional, while smaller molecules tend to cross membranes more easily [119,120]. Drugs completely absorbed (fraction absorbed >90%) have PSA values less than 60 Å2. However, they may present a high risk of toxicity, particularly those with a LogP greater than 4. These compounds are able to cross biological membranes and distribute themselves widely in tissue compartments. On the other hand, drugs with absorption below 10% have PSA values above 140 Å2 [121,122]. Dabigatran etexilate is the anticoagulant of the group with the higher molecular weight (627.7 g/mol) and PSA (154.05 Å2), while rivaroxaban is the drug with the low values for both parameters (435.9 g/mol and 88.18 Å2, respectively). Such data corroborate the fact that the first is the DOAC with the lowest bioavailability, while the second is the one with the highest. The PSA for dabigatran, apixaban, and edoxaban are respectively 150.22 Å2, 110.77 Å2, and 136.62 Å2 [41–43].