Ligand-based pharmacophore modeling and molecular dynamics driven discovery of novel MEK1 inhibitors targeting KRAS signalling pathway.

Abstract

The KRAS oncogene, which plays a crucial role in numerous human malignancies, remains a significant challenge. It is amongst the most mutated oncogenes within human cancers, specifically in pancreatic, colorectal, and non-small cell lung cancers, where it is a key driver of cancer initiation and growth. Despite its importance, KRAS is difficult to target directly due to the absence of deep binding pockets, its high affinity for GTP/GDP, and rapid cycling between active and inactive states. Thus, an effective strategy will be to target downstream effectors of KRAS, such as MEK, PI3K, and AKT. Mitogen-activated protein kinase 1 (MEK1) emerged as a promising target. In the current study, pharmacophore models were developed via a ligand-based pharmacophore approach and validated by using the Ligand Pharmacophore Mapping tool by calculating the EF1%, EF5%, EF10%, BEDROC and GH scores. Then, pharmacophore-based virtual screening was performed for the identification of novel hit molecules. A total of 22042 novel hit molecules were obtained, further narrowed to 2430 hit molecules through ADMET and Toxicity screening. Molecular Docking studies identified three top ranked compounds, PubChem-125589749 (Rank 1), PubChem-122594448 (Rank 2) and PubChem-49842405 (Rank 3), with score -76.91, -75.54 and -75.3184 kcal/mol, respectively, whereas Avutometinib showed a score of -61.78 kcal/mol. MD simulations over 100 ns and MM-GBSA calculations show that PubChem-125589749 (Rank 1) exhibited the most favourable interaction profile and stability, followed by PubChem-49842405 (Rank 3). MM-GBSA analysis of PubChem-125589749 (Rank 1) and Rank 3 showed average ΔGbinding energy -126.19 ± 15.29 and -114.81 ± 13.33. Further extended MD simulations for 200 ns and MM-GBSA calculations confirmed the binding stability and binding energy over a longer time. The reproducibility of the MD simulations was assessed by performing an independent MD simulation of the complexes and analysing the results.