Computer‐Aided Drug Design

Deng, Jinxia N.

doi:10.1002/9781119847281.ch18

Cited by 5 publications

(2 citation statements)

References 128 publications

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“…Computational chemistry employing a variety of techniques and software enables the investigation of interactions between potential drugs and biomolecules. This field has found wide-ranging applications in the pharmaceutical industry. − Over the years, numerous computational chemistry applications have been developed, including molecular and drug design, , docking simulations, ligand-based approaches such as ADMET, density functional theory (DFT), structure similarity, and pharmacophore assessment …”

Section: Introductionmentioning

confidence: 99%

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

Eissa,

Yousef,

Elkaeed

et al. 2024

ACS Omega

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Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation. Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA’s binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations. Results: DFT studies indicated T-1-PMPA’s reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA’s safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib’s values (84 and 74%), respectively. Conclusion: In conclusion, our study’s findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.

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Section: Introductionmentioning

confidence: 99%

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

Eissa,

Yousef,

Elkaeed

et al. 2024

ACS Omega

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“…12 In the field of drug discovery and development, the study of structure-activity relationships is an important factor in the creation of effective drugs. [13][14][15] Computer Assisted Drug Discovery (CADD) depends on the relationships between a drug's chemical structure and its biological activity that could be applied to optimize drug-likeness, pharmacokinetics, and pharmacodynamics. 16 CADD has become an increasingly important tool in the pharmaceutical industry, where it is used to speed up the drug discovery process and reduce costs.…”

Section: Introductionmentioning

confidence: 99%

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

Eissa,

Yousef,

Elkaeed

et al. 2023

Evol Bioinform Online

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The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA’s total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA’s correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.

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A new anticancer derivative of the natural alkaloid, theobromine, as an EGFR inhibitor and apoptosis inducer

Eissa,

G.Yousef,

Elkady

et al. 2023

Theor Chem Acc

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Computer‐Aided Drug Design

Cited by 5 publications

References 128 publications

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

A new anticancer derivative of the natural alkaloid, theobromine, as an EGFR inhibitor and apoptosis inducer

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