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

Priyanka Ramesh,Shanthi Veerappapillai

doi:10.3390/molecules27051590

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.

Highlights

Cancer is a worldwide life-threatening concern that is characterized by uncontrolled and progressive cellular divisions
Five drug-like candidates were identified using an FBDD technique for treating breast cancer patients by targeting DNA methyltransferase protein [17]. In light of these findings, we propose a hierarchical workflow of computational fragment-based drug designing, the binding free energy calculations, and dynamic simulation approaches for designing molecules against Rearranged during transfection (RET) proteins
It is evident from the literature that the heavy-atom root mean square deviation (RMSD) of the docked poses is considered as a docking success if the pose RMSD is less than 2.0 Å from the input ligand structures [40]

Summary

Introduction

Cancer is a worldwide life-threatening concern that is characterized by uncontrolled and progressive cellular divisions. It is the largest cause of mortality in the world, with 15 million new cases and 8.2 million deaths per year [1]. The activation of RET protein involves the formation of ternary complexes with glial cell line-derived neurotrophic factors and its co-receptors, autophosphorylation of tyrosine kinase domain of RET, and resulting in the activation of downstream pathways that are implied in cell growth, differentiation, and proliferation [3]. Medullary thyroid cancer, and non-small cell lung cancer (NSCLC) patients have been reported to contain a high frequency of RET mutations

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