In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

Abstract

The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.

Identifying druggable targets from active constituents of Azadirachta indica A. Juss. for non‐small cell lung cancer using network pharmacology and validation through molecular docking

“…The common type of BRAF mutation is BRAF V600E which is responsible for NSCLC 39 . Targeted therapy of B‐Raf protein is a key therapeutic strategy for NSCLC 40,41 . Somatic mutations in the PIK3CA gene have been found in high frequency in numerous cancer types, including colon, brain, stomach, breast and ovary.…”

“…therapeutic strategy for NSCLC. 40,41 Somatic mutations in the PIK3CA gene have been found in high frequency in numerous cancer types, including colon, brain, stomach, breast and ovary. More than 75% of these mutations are found in the PIK3CA gene's helical (exon 9) and kinase domains (exon 20).…”

Integration of In Silico Strategies for Drug Repositioning towards P38α Mitogen-Activated Protein Kinase (MAPK) at the Allosteric Site

“…The protein-ligand complex coordinates of the two screened drugs and the inhibitor prototype from molecular docking were dynamically modeled under the periodic boundary condition with the isothermal-isobaric (NPT) scheme [ 24 , 25 , 26 , 27 , 28 ]. The AMBER ff14SB and generalized AMBER force field version 2 (GAFF2) [ 29 ] were selected for a force field governing bonded and nonbonded interaction parameters.…”

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches

“…Similarly, there are multiple other drug repurposing frameworks which have been deployed for viral diseases such as viral cancers. Molecular dynamics, 205,213–217 a computer simulation method for observing the allowed interaction of atoms and molecules over certain period has also been used in drug repurposing for virus associated cancers Figure 6A. Molecular dynamics is used as a standalone approach or in combination with ML and DL approaches (Figure 5C).…”