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Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Typically, the hydrophilic/hydrophobic character of a drug determines how readily it will be absorbed. The size of the molecule also has an influence on drug absorption. As well as physical constraints, larger molecules are likely to contain more polar functional groups, so in principle are less-readily absorbed through cell membranes. Certain criteria have been postulated for an orally active drug to be effective, known as Lipinski’s rule of five: so-called because the numbers involve multiples of five. The drug’s molecular weight must be less than 500 g mol−1, it must have no more than five hydrogen bond donor groups, and no more than ten hydrogen bond acceptor groups, and have a log P value less than five (measure of hydrophobicity).
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
Lipinski’s rule of five is a guideline for oral bioavailability and has probably been the most influential concept in preclinical drug development (Lipinski et al., 2001). It shows that poor absorption or permeability of a compound are more likely when there are more than five hydrogen bond donors, the molecular mass is more than 500 Da, the lipophilicity is high, and the sum of nitrogen and oxygen atoms is more than 10. Although the rules do not cover some drugs, such as natural products, SNIPERs and PROTACs violate at least the condition of molecular mass. Therefore, it is necessary to improve the bioavailability of SNIPERs and PROTACs for clinical use. It is noteworthy that an orally bioavailable AR PROTAC (ARV-110) that demonstrated efficacy against prostate cancer was presented at the 2018 Genitourinary Cancers Symposium (Neklesa et al., 2018). More optimization of degraders at the linker or the combination of ligands would be more effective to improve their bioavailability. A cell-penetrating peptide might also be helpful.
Bioavailability of inhaled compounds
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Most of the commercially available compounds formulated specifically for inhalation follow the Lipinski rule of five in terms of molecular weight and LogP, including anticholinergic compounds, corticosteroids, muscarinic agonists, and β-2 agonists. However, other commercially available compounds such as insulin, leuprolide acetate, and growth hormone have molecular weights significantly higher than the 500 g/moL proposed by Lipinski. Since these compounds are intended for systemic action, their aerosol deposition is usually intended to target the alveolar region, where its large surface area (approximately 75 m2) offers high capacity for solute exchange due to the ultra-thin alveolar epithelium and excellent vascularization (3,17,18). In contrast, the other compounds that have been used off label in clinical settings or in preclinical studies do not follow the Lipinski rule of five in terms of molecular weight, (123–145,782 g/moL) and LogP (–7.4–7.6), but these may not be a limitation for their commercial development as noted for compounds such as insulin and growth hormone.
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Khalid A. Agha, Nader E. Abo-Dya, Abdul Rashid Issahaku, Clement Agoni, Mahmoud E. S. Soliman, Eatedal H. Abdel-Aal, Zakaria K. Abdel-Samii, Tarek S. Ibrahim
Upon administration of a drug, the pharmacokinetics and the physicochemical properties of the drug influence their rate of absorption, distribution, metabolism, and excretion in human system.44–46 The Lipinski’s rule of five is generally used to predict the drug-likeness of a chemical compound by measuring the biological activity, good oral bioavailability together with the compound’s tendency to cross various aqueous and lipophilic barriers by adhering to certain conditions.47,48 SwissADME was used to predict the pharmacokinetic and physicochemical properties of the compounds. As shown in Table 6, all the compounds had molecular weight less than 500 Da, octanol-water partition coefficient of less than 5, H-bond donors less than 5, and H-bond acceptors of less than 10 together with high gastro-intestinal absorption. However, one of the principal conditions that need to be met by all potential nootropic drugs is the ability to traverse the blood–brain barrier (BBB). All targets 3c-j have LogP in the range 1.5–2.36, this value is optimal for BBB penetration as postulated by Hansch and Leo that found that BBB penetration is optimal when the LogP values are in the range of 1.5–2.7, while compound 3 b did not met this value (LogP = 0.94).49 We then selected the best compound according to its docking score 3i (−4.5 kcal/mol) for molecular dynamics simulation relative to the native ligand glycine.
Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Asmaa A. Mandour, Ibrahim F. Nassar, Mohammed T. Abdel Aal, Mahmoud A. E. Shahin, Wael A. El-Sayed, Maghawry Hegazy, Amr Mohamed Yehia, Ahmed Ismail, Mohamed Hagras, Eslam B. Elkaeed, Hanan M. Refaat, Nasser S. M. Ismail
Lipinski’s rule of five is an essential tool for rational drug design. The low permeability or poor absorption for tested compounds was related to a disturbance in one of Lipinski’s rules of five42. Molecular weight, LogP, and the number of hydrogen bond acceptors (NHBAs) should lie within the values of <500, 3, and 10, respectively. Hereby, all the compounds except compound 8 had NHBAs of 10 or more. Compounds 11, 14, and 15 showed low aqueous solubility and poor absorption. Where it was observed from log S results that all the tested drugs showed non-aqueous solubility values in the range of −5.401 to −4.731 compared to the control drug (optimal: −4–0.5 log mol/L). While, the logP results showed optimal lipophilicity values (Optimal: 0 < LogP < 3) (Table 7).
Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Tony Eight Lin, Li-Chin Sung, Min-Wu Chao, Min Li, Jia-Huei Zheng, Tzu-Ying Sung, Jui-Hua Hsieh, Chia-Ron Yang, Hsueh-Yun Lee, Er-Chieh Cho, Kai-Cheng Hsu
Approved BTK inhibitors have been developed for oral administration5. To determine oral bioavailability of the top four analogous with favourable BTK inhibitory activity, predictions regarding their absorption, distribution, metabolism, excretion, and toxicity was performed (Supplementary Table 2). The compounds fit the Lipinski rule of five, suggesting that these compounds have favourable properties for oral bioavailability. Absorption of an oral drug occurs with the gastrointestinal system. The human intestinal absorption for a particular drug is an important property to gauge whether a small molecule can be delivered to its target40. Three of the compounds show favourable absorption levels (Supplementary Table 2). Further, the most potent compound, NSC725686, has the most favourable QED score, suggesting that it is the most drug-like compound. Compound NSC725686 contains an imine linker that may be cleaved in an acidic environment of the gastrointestinal tract. Exploring different formulations may be a strategy to avoid hydrolysis and to maintain potency. Our docking analysis suggests that the imine group does not make significant interactions to the target binding site (Figure 5). Further studies would explore modifications to the imine linker and optimisation of NSC725686 as a potential BTK inhibitor.