Related Experiment Video
Updated: Jan 24, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Virtual screening of p53 mutants reveals Y220S as an additional rescue drug target for PhiKan083 with higher binding
Vaijayanthi Raghavan1, Maulishree Agrahari2, Dhananjaya Kale Gowda3
1Dept. of Biotechnology, 100 ft. Ring Road, Banashankari 3(rd)stage, PES University, Bengaluru, 560085, India.
Abstract:
Pharmacological intervention to reactivate p53 in human tumors holds great promise for cancer patients. A number of small molecules that reactivate p53 mutants that are either specific to certain mutation or more broadly on various mutants of p53 are discovered by rational design and screening methods. One of the most remarkable among small molecules for the rescue of specific mutant p53, Y220C is PhiKan083 (1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine) that have been demonstrated effective in advanced pre-clinical trials. Our attempt here is to identify additional targets of p53 mutants for rescue drugs and provide insight into the molecular level interactions of the drug with the mutant target. In this study PhiKan083 also known as PK083 is investigated, screened and validated on 28 different mutants of p53 using FlexX. Interaction of PhiKan08 with Y220C is found to be largely hydrophobic and a crucial single H-bond interaction with Asp228 in addition to few electrostatic interactions. Our study identified Y220S mutant as an additional target for PK083 as it shows a similar interaction pattern. Besides this, Docking and MD simulation studies, showed that Y220S binds to PK083 at higher efficiency as a result of improved steric and hydrophobic environment in the binding cavity in comparison with known mutant target, Y220C. Further, we point out that structure guided optimization of PhiKan08 can lead to an improved drug that can interact favourably with yet another mutant, Y220 N. In addition, this study revealed that Y220H and other mutants including native p53 does not provide any favourable interaction with PhiKan08 which is in accord with the experimental findings. These findings can facilitate the selection of patients for clinical studies and cancer survival analysis.
Related Concept Videos
01:18Additional Routes of Drug Administration
Administering drugs via inhalation allows for the direct delivery of gaseous, volatile substances or droplets to different parts of the respiratory tract. One of the advantages of the inhalation route is the rapid absorption of drugs into the circulatory system, which is possible because of the large surface area of...
01:18Factors Affecting Protein-Drug Binding: Drug-Related Factors
One crucial factor in drug-protein binding is the drug's lipophilicity or its affinity for fat. More lipophilic drugs tend to have higher binding extents. For example, highly lipophilic drugs like cloxacillin exhibit substantial protein binding, with as much as 95% of the drug binding to proteins. In...
01:24Tissue-Drug Binding: Localization of Drugs and its Significance
Drugs can bind to different tissue components, enhancing their distribution and localization. The factors influencing drug localization in tissues include the drug's lipophilicity, structural characteristics, tissue perfusion rate, and pH differences. These factors determine...
01:23Factors Affecting Protein-Drug Binding: Drug Interactions
Displacement interactions can have varying outcomes, ranging from toxicity to virtually...
01:30Drug Binding to Blood Components
HSA is the most abundant plasma protein and is vital in drug binding. It contains distinct drug-binding sites, with different drugs exhibiting affinity for specific sites. There are three main drug-binding domains for HSA: sites I, II, and III. These domains are...
01:21Drug Distribution: Tissue Binding
For...