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Updated: Dec 3, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A molecular dynamics and docking study to screen anti-cancer compounds targeting mutated p53
Hetal Damani Shah1, Dhananjaya Saranath2, Vinuthaa Murthy3
1Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed-to-be) University, Vile Parle (West), Mumbai, India.
Abstract:
The p53 gene is mutated in greater than 50% of several human cancers including bladder urothelial carcinoma, lung adenocarcinoma, colorectal carcinoma, and oral cancer. Mutations in the p53 gene occur predominantly in the DNA-binding domain causing loss of function and accumulation of dysfunctional p53 protein in tumors by hetero-oligomerization with the wild type p53. Thus an in silico approach for the rational design of potent, pharmacologically active small drug-like compounds targeting mutated p53 was undertaken. Molecular dynamics simulations of the wild type p53 monomer and p53 mutants R175H and R248Q were performed using Discovery Studio v3.5. Phase was used to generate pharmacophore models and the sitemap generated pocket was used to screen the Maybridge HitFinderTM library using Schrodinger Suite. We identified ten compounds (Cmpd-1 to Cmpd-10) that showed preferential binding to p53 mutants, and their pharmacokinetic profiles complied with the ADMET rules. Cmpd-4 and Cmpd-8 demonstrated binding with mutated p53 at cysteine 124, similar to the mutant p53 reactivating compound APR-246 (PRIMA-1Met) for functional restoration of the mutant p53. We propose the identified compounds as suitable drug candidates against mutated p53 protein, with the specific small drug-like molecules as either single drugs or in combination with lower doses of additional cytotoxic drugs, consequently reducing adverse side effects in patients.Communicated by Ramaswamy H. Sarma.
Insights
Researchers designed small drug molecules targeting mutated p53 protein, common in many cancers. Ten compounds showed preferential binding to mutant p53, with potential for new cancer therapies and reduced side effects.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- The p53 tumor suppressor gene is frequently mutated in over 50% of human cancers, leading to loss of function.
- Mutations often occur in the DNA-binding domain, resulting in dysfunctional p53 protein accumulation.
- Targeting mutated p53 is a critical strategy for developing novel cancer therapeutics.
Purpose of the Study:
- To rationally design potent, pharmacologically active small drug-like compounds targeting mutated p53 using an in silico approach.
- To identify novel drug candidates with preferential binding to common p53 mutants.
- To evaluate the potential of these compounds as single agents or in combination therapies.
Main Methods:
- Molecular dynamics simulations were performed on wild-type p53 and mutants R175H and R248Q.
- Pharmacophore models were generated using Phase, and a sitemap pocket was used for virtual screening.
- The Maybridge HitFinder library was screened using Schrodinger Suite to identify potential binders.
Main Results:
- Ten compounds (Cmpd-1 to Cmpd-10) were identified with preferential binding to mutated p53.
- All identified compounds met ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) rules for pharmacokinetic profiles.
- Compounds Cmpd-4 and Cmpd-8 showed binding at cysteine 124, similar to the known mutant p53 reactivating agent APR-246.
Conclusions:
- The identified small molecules are promising drug candidates for targeting mutated p53.
- These compounds could serve as single agents or in combination with cytotoxic drugs to reduce adverse effects.
- This study highlights the potential of in silico drug design for developing targeted cancer therapies.
