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Prospects of Pre-clinical [6.6.0] Bicyclic Nitrogen Heterocycles in the Treatment of Tuberculosis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Neha P. Agre, Mariam S. Degani, Sanjib Bhakta
The ADME and medicinal chemistry properties of the 10 most potent compounds containing the quinoxaline scaffold are depicted in Table 2. The properties were predicted using SWISSADME program of Swiss Institute of Bioinformatics (Daina et al. 2017). The important pharmacokinetic parameters like GI absorption, BBB permeation, and CYP inhibition as well as relevant medicinal chemistry properties like Lipinski’s rule of 5 (Ro5) (Lipinski et al. 2012), PAINS (Baell and Holloway 2010), and Brenk (Brenk et al. 2008) and Lead-likeness (Teague et al. 1999) that determine the drug-likeness of the molecules were predicted. A compound, to have the ideal pharmacokinetics and medicinal chemistry properties, should exhibit a high GI absorption, no BBB permeation (for molecules not targeted for CNS diseases, to avoid CNS side effects), no CYP enzyme inhibition and comply with Lipinski’s Ro5. Moreover, it should show alert in PAINS (pan assay interference compounds) filter, 0 alert in Brenk filter (structural fragments identified to be putatively toxic, chemically reactive, metabolically unstable or to bear properties responsible for poor pharmacokinetics) and should comply with the lead-likeness filter (250 ≤ molecular weight ≤ 350, XLOGP ≤ 3.5, rotatable bonds ≤ 7).
In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Chao-Di Chang, Min-Wu Chao, Hsueh-Yun Lee, Yi-Ting Liu, Huang-Ju Tu, Ssu-Ting Lien, Tony Eight Lin, Tzu-Ying Sung, Shih-Chung Yen, Sing-Han Huang, Kai-Cheng Hsu, Shiow-Lin Pan
Compounds were obtained from the ChemDiv database (https://www.chemdiv.com/) for virtual screening. Compounds were then filtered by drug-like properties. The quantitative estimate of drug-likeness (QED), which provides a quantitative method for determining the drug-likeness properties of each compound, was calculated30. In this study, compounds with QED score of <0.25 were removed. Lipinski and Veber’s rules were then applied to select compounds more likely to be absorbed, distributed, metabolised, and excreted by the human body31–33. Potential pan-assay interference compounds (PAINS) were further removed because these compounds are often false positives34. The remaining compounds were then docked into the binding site of MAP4K4 using a molecular docking program, LeadIT35. LeadIT was designed based on an interaction model LUDI36, which calculates interactions between a compound and residues of a binding site. Docking poses and score of compounds were generated by LeadIT. All docking parameters used the default settings. The crystal structure of MAP4K4 (PDB ID: 4OBP) was downloaded from the RCSB Protein Data Bank37. Water molecules in the protein structure were removed. The binding site was determined to be 12 Å from the co-crystal ligand (HET ID: 2QU). Compounds were protonated in an aqueous solution and docked to the binding site using the default settings.
Synthesis and biological evaluation of halogenated phenoxychalcones and their corresponding pyrazolines as cytotoxic agents in human breast cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Peter A. Halim, Rasha A. Hassan, Khaled O. Mohamed, Soha O. Hassanin, Mona G. Khalil, Amr M. Abdou, Eman O. Osman
As an important point to discuss α,β-unsaturated compounds, as Michael acceptors, are of special interest due to their ability to undergo irreversible covalent interaction with MAPK leading to its inhibition55. However, the possibility of being pan assay interference compounds (PAINS) may be an obstacle to many researchers. PAINS are considered as useless compounds in the drug discovery process as they show activity in multiple types of assays56,57. However, in this study, it was found that the most active chalcone 2c with methyl substituent at R1 was 5.6-fold and 8.7-fold more active than its bioisosters 2a and 2b, respectively. Also chalcone 2f with methyl substituent at R1 was 10.6-fold and 23.6-fold more active than chalcones 2d and 2e, respectively. Moreover, the high selectivity index of compounds 2c and 2f excluded the doubt of being PAINS.
Calycosin: a Review of its Pharmacological Effects and Application Prospects
Published in Expert Review of Anti-infective Therapy, 2021
Mao Deng, Huijuan Chen, Jiaying Long, Jiawen Song, Long Xie, Xiaofang Li
In recent years, Pan-assay interference compounds (PAINS) have become one of the focuses of drug research and development. The substructure of PAINs can confer an ability to interfere with biochemical assays, so it is called ‘false positive’. Most PAINs are only chemical substances with chemical reactions, rather than real specific drug candidates. However, simply using the characteristics of PAINs to determine whether a compound is PAINs may exclude a useful compound from consideration and tag a useless compound as worthy of development [115,116]. Natural compounds are one of the main sources of PAINs [117]. CA, as a flavonoid, contains a highly active part (phenolic hydroxyl) in its structure, so whether it is PAINs should be considered. Whereas, in the pharmacological part of this review, the pharmacological activities of CA have been proved to be effective in vivo and in vitro, and have specific targets. In other words, pharmacological experiments have proved that the pharmacological effects of CA have specificity, which is different from PAINs. At present, to determine whether CA is PAINs, further clinical trials are needed to prove the pharmacological activity of CA in humans. We propose this point here, hoping to attract the attention of researchers.