A new approach used in docking study for predicting the combination drug efficacy in EML4-ALK target of NSCLC
Saleena Younus1, S S Vinod Chandra2, Junaida Ibrahim1
1Department of Computational Biology and Bioinformatics, University of Kerala, Trivandrum, India.
Abstract:
Combination drug treatments are usually used in many diseases, including cancers and AIDS. This treatment strategy is known as one of the cornerstone in therapies, which potentially reduces drug toxicity and drug resistance and also enhances therapeutic efficacy. Before using a drug in treatment, several experimental studies are done in vivo and in vitro to ensure the drug's efficacy. In such experimental studies, the drug's efficacy is evaluated with the help of drug dose ratio. In the combination drug experimental studies, the efficacy of the drugs is quantified with the Combination Index (CI) value and then interpreted by various terminologies like synergy, additive, and antagonism. Several computational models have now been invented for the speedy identification of combination drug efficacy. Unfortunately, none of these models have predicted the atomic level interaction of the combination drug with the target protein. This type of intermolecular interaction can be identified with the help of docking software. In the proposed work, we try to identify the intermolecular interaction and efficacy of the combination drug Crzizotinib and Temozolomide in the target of EML4-ALK in NSCLC by in silico study. The result of the study was evaluated with drug properties and Complex Energy (CE) of the docked complex rather than using docking score and binding energy. From this study, we could understand that first, Crizotinib and then after the Temozolomide drug binded on the EML4-ALK protein complex, showed very least CE and also identified that the combination of Crizotinib and Temozolomide drug are more effective in NSCLC.Communicated by Ramaswamy H. Sarma.
Insights
Combination drug therapy, using Crizotinib and Temozolomide, shows enhanced efficacy against Non-Small Cell Lung Cancer (NSCLC) by targeting EML4-ALK. This in silico study reveals their synergistic interaction at the atomic level.
Area of Science:
- Pharmacology
- Computational Chemistry
- Oncology
Background:
- Combination drug therapy is a cornerstone in treating diseases like cancer and AIDS, aiming to reduce toxicity and resistance while improving efficacy.
- Traditional methods evaluate drug efficacy through in vivo/in vitro studies and Combination Index (CI) values, but lack atomic-level interaction insights.
- Existing computational models for drug efficacy prediction do not detail intermolecular interactions with target proteins.
Purpose of the Study:
- To investigate the intermolecular interactions and efficacy of Crizotinib and Temozolomide combination therapy against the EML4-ALK target in Non-Small Cell Lung Cancer (NSCLC).
- To utilize in silico methods to predict atomic-level drug-target interactions, offering a deeper understanding beyond traditional efficacy metrics.
Main Methods:
- Employing in silico (computational) studies to analyze the binding of Crizotinib and Temozolomide to the EML4-ALK protein.
- Evaluating drug efficacy and interaction based on Complex Energy (CE) of the docked complex and drug properties, rather than solely relying on docking scores or binding energy.
Main Results:
- The study identified a specific binding order: Crizotinib binds first, followed by Temozolomide, to the EML4-ALK protein complex.
- The combination of Crizotinib and Temozolomide demonstrated a very low Complex Energy (CE), indicating a stable and effective interaction.
- The in silico analysis suggests that this drug combination is more effective for treating NSCLC.
Conclusions:
- The combination of Crizotinib and Temozolomide exhibits significant potential for treating NSCLC by effectively targeting the EML4-ALK pathway.
- In silico studies, focusing on Complex Energy, provide valuable insights into atomic-level drug interactions for combination therapies.
- This research highlights the efficacy of Crizotinib and Temozolomide as a potent combination therapy for NSCLC.
