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Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential
Sourav Pal1,2, Vinay Kumar1,3, Biswajit Kundu1
1Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
Abstract:
Camptothecin (CPT), a natural product and its synthetic derivatives exert potent anticancer activity by selectively targeting DNA Topoisomerase I (Top1) enzyme. CPT and its clinically approved derivatives are used as Top1 poisons for cancer therapy suffer from many limitations related to stability and toxicity. In order to envisage structurally diverse novel chemical entity as Top1 poison with better efficacy, Ligand-based-pharmacophore model was developed using 3D QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery studio 4.1 clients. The chemical features of 29 CPT derivatives were taken as the training set. The selected pharmacophore model Hypo1 was further validated by 33 test set molecules and used as a query model for further screening of 1,087,724 drug-like molecules from ZINC databases. These molecules were subjected to several assessments such as Lipinski rule of 5, SMART filtration and activity filtration. The molecule obtained after filtration was further scrutinized by molecular docking analysis on the active site of Top1 crystal structure (PDB ID: 1T8I). Six potential inhibitory molecules have been selected by analyzing the binding interaction and Ligand-Pharmacophore mapping with the validated pharmacophore model. Toxicity assessment TOPKAT program provided three potential inhibitory 'hit molecules' ZINC68997780, ZINC15018994 and ZINC38550809. MD simulation of these three molecules proved that the ligand binding into the protein-DNA cleavage complex is stable and the protein-ligands conformation remains unchanged. These three hit molecules can be utilized for designing future class of potential topoisomerase I inhibitor.
Insights
Researchers developed a new pharmacophore model to discover novel Topoisomerase I (Top1) inhibitors for cancer therapy. This model identified three promising drug candidates with stable binding and potential for future drug design.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Oncology
Background:
- Camptothecin (CPT) and its derivatives are effective Topoisomerase I (Top1) poisons for cancer treatment but have limitations in stability and toxicity.
- Developing novel Top1 inhibitors with improved efficacy and safety profiles is crucial for advancing cancer therapy.
Purpose of the Study:
- To develop a validated ligand-based pharmacophore model for identifying novel Topoisomerase I (Top1) inhibitors.
- To screen a large chemical database and identify potential drug candidates with improved properties over existing CPT derivatives.
- To assess the stability and binding interactions of identified hit molecules with Top1.
Main Methods:
- Utilized the 3D QSAR pharmacophore generation (HypoGen algorithm) with a training set of 29 CPT derivatives.
- Validated the pharmacophore model with a test set of 33 molecules and screened 1,087,724 drug-like molecules from the ZINC database.
- Applied Lipinski's rule of 5, SMART filtration, molecular docking, and toxicity assessment (TOPKAT) to identify potential inhibitors.
- Conducted molecular dynamics (MD) simulations to evaluate the stability of the identified hit molecules with the Top1-DNA complex.
Main Results:
- A validated pharmacophore model (Hypo1) was generated and used for virtual screening.
- Six potential Top1 inhibitory molecules were initially identified through pharmacophore mapping and molecular docking.
- Three 'hit molecules' (ZINC68997780, ZINC15018994, and ZINC38550809) were selected after toxicity assessment.
- MD simulations confirmed stable binding of these three hit molecules within the Top1-DNA cleavage complex.
Conclusions:
- The developed pharmacophore model is effective in identifying novel Top1 inhibitors.
- The three identified hit molecules demonstrate potential as lead compounds for developing new Top1-targeted cancer therapies.
- These novel inhibitors offer a promising avenue for overcoming the limitations of current CPT-based drugs.
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