Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

Abstract

Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies.

Machine learning driven drug repurposing strategy for identification of potential RET inhibitors against non-small cell lung cancer

“…Similarly, the density function theory analysis of the lead molecules was carried out as per the protocol reported in our recent publication [ 5 ]. In this study, the global descriptors such as energy gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), hardness, softness, ionization potential, electron affinity and chemical potential were estimated to screen the hit molecules.…”

“…Hence RET specific inhibitors pralsetinib and selpercatinib were developed to remedied the limitations of MKIs. Nevertheless, the emergence of acquired drug resistance against RET specific inhibitors due to the development of gatekeeper (V804M/L) and solvent front secondary mutations (G810A/C/R/S) have been reported in the recent times [ 5 ]. Although an adequate number of clinical trials were carried out to offset the debility of the specific inhibitors, the adverse off-target side effects and limited response durability limited its efficacy [ 6 ].…”

Machine learning driven drug repurposing strategy for identification of potential RET inhibitors against non-small cell lung cancer

“…The contribution of different energy terms to binding free energy was also investigated during the analysis. Similarly, the density function theory analysis of the lead molecules was carried out as per the protocol reported in our recent publication [5]. In this study, the global descriptors such as energy gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), hardness, softness, ionization potential, electron a nity and chemical potential were estimated to screen the hit molecules.…”

“…Hence RET speci c inhibitors pralsetinib and selpercatinib were developed to remedied the limitations of MKIs. Nevertheless, the emergence of acquired drug resistance against RET speci c inhibitors due to the development of gatekeeper (V804M/L) and solvent front secondary mutations (G810A/C/R/S) have been reported in the recent times [5]. Although an adequate number of clinical trials were carried out to offset the debility of the speci c inhibitors, the adverse off-target side effects and limited response durability limited its e cacy [6].…”