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Published on: December 1, 2016
Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid's Adroit Activity against Lung Cancer through Multitargeted Docking,
Mohammed Ageeli Hakami1, Ali Hazazi2, Fawaz Albloui2
1Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Al-Quwayiyah 19257, Saudi Arabia.
Abstract:
Lung cancer is a pervasive and challenging disease with limited treatment options, with global health challenges often present with complex molecular profiles necessitating the exploration of innovative therapeutic strategies. Single-target drugs have shown limited success due to the heterogeneity of this disease. Multitargeted drug designing is imperative to combat this complexity by simultaneously targeting multiple target proteins and pathways, which can enhance treatment efficacy and overcome resistance by addressing the dynamic nature of the disease and stopping tumour growth and spread. In this study, we performed the molecular docking studies of Drug Bank compounds with a multitargeted approach against crucial proteins of lung cancer such as heat shock protein 5 (BIP/GRP78) ATPase, myosin 9B RhoGAP, EYA2 phosphatase inhibitor, RSK4 N-terminal kinase, and collapsin response mediator protein-1 (CRMP-1) using HTVS, SP with XP algorithms, and poses were filtered using MM\GBSA which identified [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BenCarMethIn YlPro-Phosphonic Acid) (DB02504) as multitargeted drug candidate with docking and MM\GBSA score ranges from -5.83 to -10.66 and -7.56 to -50.14 Kcal/mol, respectively. Further, the pharmacokinetic and QM-based DFT studies have shown complete acceptance results, and interaction fingerprinting reveals that ILE, GLY, VAL, TYR, LEU, and GLN were among the most interacting residues. The 100 ns MD simulation in the SPC water model with NPT ensemble showed stable performance with deviation and fluctuations <2 Å with huge interactions, making it a promising multitargeted drug candidate; however, experimental studies are needed before use.
Insights
This study identifies a promising multitargeted drug candidate, [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (DB02504), for lung cancer treatment. Computational analyses confirm its potential to overcome drug resistance and inhibit tumor growth.
Area of Science:
- Computational drug discovery
- Molecular modeling
- Pharmacology
Background:
- Lung cancer presents complex molecular profiles and limited treatment options, often necessitating innovative therapeutic strategies.
- Single-target drugs show limited efficacy due to disease heterogeneity, highlighting the need for multitargeted approaches.
- Multitargeted drug design can enhance efficacy and overcome resistance by simultaneously inhibiting multiple cancer-related proteins and pathways.
Purpose of the Study:
- To identify a novel multitargeted drug candidate for lung cancer using molecular docking and simulation.
- To evaluate the efficacy of potential drug compounds against key lung cancer proteins.
- To assess the pharmacokinetic properties and stability of promising drug candidates.
Main Methods:
- Molecular docking studies were performed using HTVS, SP, and XP algorithms against lung cancer targets: BIP/GRP78 ATPase, myosin 9B RhoGAP, EYA2 phosphatase, RSK4 kinase, and CRMP-1.
- Drug Bank compounds were screened, and promising candidates were filtered using MM\GBSA.
- Pharmacokinetic, QM-based DFT, and 100 ns MD simulations were conducted to assess drug stability and interactions.
Main Results:
- [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (DB02504) was identified as a potent multitargeted drug candidate.
- Docking and MM\GBSA scores ranged from -5.83 to -10.66 and -7.56 to -50.14 Kcal/mol, respectively.
- MD simulations showed stable performance (<2 Å deviation), indicating significant interactions with target proteins, with ILE, GLY, VAL, TYR, LEU, and GLN being key residues.
Conclusions:
- DB02504 demonstrates significant potential as a multitargeted drug candidate for lung cancer, showing promising computational results.
- The compound's ability to interact with multiple targets suggests a strategy to overcome drug resistance and inhibit tumor progression.
- Further experimental validation is required to confirm the therapeutic efficacy of DB02504 in lung cancer treatment.
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