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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.
Assessment of Quercetin Isolated from Enicostemma Littorale Against Few Cancer Targets: An in Silico Approach
Published in A. K. Haghi, Ana Cristina Faria Ribeiro, Lionello Pogliani, Devrim Balköse, Francisco Torrens, Omari V. Mukbaniani, Applied Chemistry and Chemical Engineering, 2017
Lipinski’s rule of five is a rule of thumb to evaluate drug likeness, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules.44 Lipinski’s rule says that, in general, an orally active drug has no more than one violation of the following criteria:Not more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)Not more than ten hydrogen bond acceptors (nitrogen or oxygen atoms)A molecular mass not greater than 500 daltonsAn octanol-water partition coefficient40log P not greater than five.
In silico design of PDHK inhibitors: From small molecules to large fluorinated compounds
Published in Tanmoy Chakraborty, Prabhat Ranjan, Anand Pandey, Computational Chemistry Methodology in Structural Biology and Materials Sciences, 2017
The acceptability of the proposed drug molecules was also analyzed in terms of Lipinski’s rule of five [19]. This is a rule of thumb to evaluate drug likeness, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. Poor absorption or permeation are more likely when a ligand violates Lipinski’s rule of five, i.e. has more than five hydrogen donors, the molecular weight is over 500, the logP is over 5, and the sum of N’s and O’ s is over 10.
A Bayesian method for concurrently designing molecules and synthetic reaction networks
Published in Science and Technology of Advanced Materials: Methods, 2023
Qi Zhang, Chang Liu, Stephen Wu, Yoshihiro Hayashi, Ryo Yoshida
As target properties , we considered the following two physicochemical properties that quantitatively express the drug-likeliness of a designed molecule . QED The quantitative estimate of drug-likeness (QED) quantifies drug-likeness as a score ranging between 0 and 1 [37]. QED was modeled on a dataset of 771 known oral drugs using eight descriptors, including molecular weight, polar surface area, and number of hydrogen bond donors and acceptors. The higher the QED value, the more drug-like the molecule is judged to be. The target range of the QED was set to be greater than 0.8.logP The octanol-water partition coefficient logP is defined as the normal logarithm of the ratio of the concentrations of molecules in the organic and aqueous layers at equilibrium. According to Lipinski’s rule of five [49], the target range of logP was defined as not exceeding 5.
Theoretical validation of some third-generation epidermal growth factor receptor (EGFR) Inhibitors as non-small cell lung cancer (NSCLC) drugs
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Muhammad Tukur Ibrahim, Adamu Uzairu
The drug-like features of the hit compounds were assessed adopting the prominent Lipinski’s rule of five (Molecular weight≤500, Number of hydrogen bond donors≤5, Number of hydrogen bond acceptors≤10, and Calculated MLog p ≤ 5) using SwissADME web server (Table 3). The modeled drug-like features showed only 1 violation for all the reported compounds (they all have molecular weight greater than 500). Their number of hydrogen bond donors, number of hydrogen bond acceptors and the calculated MLog p values were all within the accepted range. Based on this screening conditions, the recognized hit compounds were ascertained to be drug-like (druggable) by not violating more than the threshold values set for the Lipinski’s rule of five. Furthermore, according to the value of their bioavailability score (0.55), they were all further established to be orally bioavailable. Generally, these recognized hit compounds were predicted not to have any issue associated to their bioavailability.
MOLECULAR DOCKING INVESTIGATION AND PHARMACOKINETIC PROPERTIES PREDICTION OF SOME ANILINOPYRIMIDINES ANALOGUES AS EGFR T790M TYROSINE KINASE INHIBITORS
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Muhammad Tukur Ibrahim, Adamu Uzairu, Gideon Adamu Shallangwa, Sani Uba
Compounds 1, 3, 9, 15, and 30 among the reported compounds respect the Lipinski’s rule of five without violating any of the condition set by the rule (Molecular weight ≤ 500, Number of hydrogen bond donors ≤ 5, Number of hydrogen bond acceptors ≤ 10, and Calculated Log p ≤ 5). While other reported compounds were found to have one violation (that is their molecular weight was greater than 500) but still within the permissible limit for drug molecule to be orally bioavailable. All the compounds have good bioavailability score of 0.55 which further confirmed the drug-likeness properties of these reported compounds (Table 3). As such the reported compounds are said to be orally bioavailable with good pharmacokinetic profiles.