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Updated: Aug 27, 2025
Nano-Differential Scanning Fluorimetry for Screening in Fragment-based Lead Discovery
Published on: May 16, 2021
New lead compounds identification against KRas mediated cancers through pharmacophore-based virtual screening and
Mehreen Ghufran1,2, Ashfaq Ur Rehman3, Muhammad Ayaz4
1Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, Pakistan.
Abstract:
Cancer remains the leading cause of mortality and morbidity in the world, with 19.3 million new diagnoses and 10.1 million deaths in 2020. Cancer is caused due to mutations in proto-oncogenes and tumor-suppressor genes. Genetic analyses found that Ras (Rat sarcoma) is one of the most deregulated oncogenes in human cancers. The Ras oncogene family members including NRas (Neuroblastoma ras viral oncogene homolog), HRas (Harvey rat sarcoma) and KRas are involved in different types of human cancers. The mutant KRas is considered as the most frequent oncogene implicated in the development of lung, pancreatic and colon cancers. However, there is no efficient clinical drug even though it has been identified as an oncogene for 30 years. Therefore there is an emerging need to develop potent, new anticancer drugs. In this study, computer-aided drug designing approaches as well as experimental methods were employed to find new and potential anti-cancer drugs. The pharmacophore model was developed from an already known FDA approved anti-cancer drug Bortezomib using the software MOE. The validated pharmacophore model was then used to screen the in-house and commercially available databases. The pharmacophore-based virtual screening resulted in 26 and 86 hits from in-house and commercial databases respectively. Finally, 6/13 (in-house database) and 24/64 hits (commercial databases) were selected with different scaffolds having good interactions with the significant active residues of KRasG12D protein that were predicted as potent lead compounds. Finally, the results of pharmacophore-based virtual screening were further validated by molecular dynamics simulation analysis. The 6 hits of the in-house database were further evaluated experimentally. The experimental results showed that these compounds have good anti-cancer activity which validate the protocol of our in silico studies. KRasG12D protein is a very important anti-cancer target and potent inhibitors for this target are still not available, so small lead compound inhibitors were identified to inhibit the activity of this protein by blocking the GTP-binding pocket.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified novel small molecule inhibitors targeting the KRasG12D protein, a key driver in many cancers. These potent compounds, discovered through computational screening and validated experimentally, offer a promising new avenue for developing effective anti-cancer drugs.
Area of Science:
- Oncology and Drug Discovery
- Computational Chemistry and Molecular Modeling
Background:
- Cancer is a leading cause of global mortality, driven by genetic mutations in oncogenes like Ras.
- Mutant KRas (Kirsten rat sarcoma viral oncogene homolog) is frequently implicated in lung, pancreatic, and colon cancers, yet effective drugs remain elusive despite decades of research.
- There is a critical need for novel, potent anticancer therapeutics targeting KRas.
Purpose of the Study:
- To identify novel small-molecule inhibitors targeting the KRasG12D protein.
- To employ a combination of computer-aided drug design and experimental validation for drug discovery.
Main Methods:
- Development of a pharmacophore model using MOE software based on Bortezomib.
- Virtual screening of in-house and commercial compound databases using the validated pharmacophore model.
- Molecular dynamics simulations for validating screening results and experimental evaluation of selected lead compounds.
Main Results:
- Pharmacophore-based virtual screening identified 26 and 86 hits from in-house and commercial databases, respectively.
- Selected lead compounds demonstrated favorable interactions with key active residues of the KRasG12D protein's GTP-binding pocket.
- Experimental evaluation of six compounds from the in-house database confirmed significant anti-cancer activity.
Conclusions:
- The study successfully identified potent small-molecule inhibitors for the KRasG12D oncoprotein.
- The computational and experimental approach validated the efficacy of the identified lead compounds.
- These findings provide a strong foundation for developing new targeted therapies against KRas-driven cancers.
