Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies

Nada, Hossam; Kim, Sung-Do; Godesi, Sreenivasulu; Lee, Joohan; Lee, Kyeong

doi:10.1080/07391102.2022.2164061

Cited by 8 publications

(19 citation statements)

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“…The more an atom deviates from its average position, the more flexible or mobile it is. RMSF can be used to identify the regions of the protein that are flexible and mobile, which may be important for binding and activity . Furthermore, RMSF can be used to identify regions of the protein that are important for specificity.…”

Section: Resultsmentioning

confidence: 99%

“…The RMSD values provide a measure of the structural similarity between the initial and final structures of the protein–ligand complexes, allowing for an assessment of the stability of the complexes over the course of the simulation. , Additionally, by comparing the simulation results to the unbound protein state and a known complex, the validity of the simulation protocol can be evaluated. This approach provides a more accurate picture of the binding interactions and stability of the complexes, taking into account the dynamic nature of the protein and the ligand in solution …”

Section: Resultsmentioning

confidence: 99%

“…After relaxation, the systems underwent a 5 ns molecular dynamics (MD) simulation in the NPT ensemble, using a Nose–Hoover thermostat and Martyna–Tobias–Klein barostat ( T = 300 K, thermostat relaxation time = 1.0 ps; P = 1 atm; barostat relaxation time = 2.0 ps). The MD simulation results were analyzed using QtGrace and Microsoft Excel …”

Section: Methodsmentioning

confidence: 99%

“…41 Particle mesh Ewald (PME) was used to handle electrostatic interactions, whereas periodic boundary conditions (PBC) and a 9.0 Å (Angstrom) cutoff were used for nonbond interactions. 30 Each MD simulation was prepared employing a six-step relaxation protocol, which included 2000 steps of LBFGS minimization where the solute was restricted and a 50 kcal mol −1 Å −1 loose convergence criteria was applied. This was followed by two quick 12 ns simulations of temperature and pressure at T = 10 K (thermostat relaxation constant = 0.1 ps) and P = 1 atm (barostat relaxation constant = 50 ps) where nonhydrogen solute atoms were restrained.…”

Section: Dft Calculationsmentioning

confidence: 99%

“…The MD simulation results were analyzed using QtGrace and Microsoft Excel. 30 4.6. MM-GBSA Calculations.…”

Section: Dft Calculationsmentioning

confidence: 99%

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Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library

et al. 2023

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Cancer is characterized by altered cellular metabolism, and metabolic enzymes are considered as a promising target for anticancer therapy. Pyrimidine metabolism dysregulation is associated with various types of cancer, particularly lung cancer, which is one of the leading causes of cancer-related mortality worldwide. Recent studies have shown that small-cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and are sensitive to its disruption. DHODH, the rate-limiting enzyme of the de novo pyrimidine production pathway, is essential in the production of RNA and DNA and is overexpressed in malignancies such as AML, skin cancer, breast cancer, and lung cancer, thereby highlighting DHODH as a viable target for developing drugs to combat lung cancer. Herein, rational drug design and computational techniques were used to discover novel DHODH inhibitors. A small combinatorial library was generated, and the top hits were synthesized and tested for anticancer activity against three lung cancer cell lines. Among the tested compounds, compound 5c possessed a stronger cytotoxicity (TC 50 of 11 μM) compared to the standard FDA-approved drug (Regorafenib, TC 50 of 13 μM) on the A549 cell line. Furthermore, compound 5c demonstrated potent inhibitory activity against hDHODH at a nanomolar level of 421 nM. DFT, molecular docking, molecular dynamic simulations, and free energy calculations were also carried out to understand the inhibitory mechanisms of the synthesized scaffolds. These in silico studies identified key mechanisms and structural features that will be crucial for future studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Dft Calculationsmentioning

confidence: 99%

“…The MD simulation results were analyzed using QtGrace and Microsoft Excel. 30 4.6. MM-GBSA Calculations.…”

Section: Dft Calculationsmentioning

confidence: 99%

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Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library

et al. 2023

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Chalcone‐based benzenesulfonamides as potent and selective inhibitors for human carbonic anhydrase II: Design, synthesis, in vitro, and in silico studies

Lee,

Elkamhawy,

Al‐Karmalawy

et al. 2024

Archiv der Pharmazie

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Sulfonamides are promising classical carbonic anhydrase (CA; EC 4.2.1.1) inhibitors, being used for several medical purposes such as diuretics, anticonvulsants, topically acting antiglaucoma agents, for antiobesity and anticancer therapies. Herein, a series of chalcone‐based benzenesulfonamides (3a‒m) was synthesized and assessed for its inhibitory activity against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX, and XII). Most compounds displayed single‐ to double‐digit nanomolar inhibition constants (Kis), with some derivatives being more potent and/or selective than the standard drug acetazolamide (AAZ). Among the synthesized compounds, 3g compound demonstrated the highest inhibitory activity against the hCA II isoform (Ki = 2.5 nM) with 30‐, 9‐, and 11‐fold selectivity for hCA II over the I, IX, and XII isoforms, respectively. Structure–activity relationships for different substitution patterns were analyzed. Additionally, a molecular docking study showed that compound 3g bound to hCA II by coordinating with the zinc ion through the deprotonated benzenesulfonamide moiety, in addition to a hydrogen bond formed between an oxygen of the sulfonamide moiety and Thr199. Moreover, the chalcone core participated in van der Waals interactions with some active site residues, such as Ile91, Val121, and Leu198. Consequently, this report introduces a successful approach toward identifying compound 3g as a highly potent and selective chalcone‐based benzenesulfonamide inhibitor of hCA II worthy of further investigation.

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Machine Learning-Based Approach to Developing Potent EGFR Inhibitors for Breast Cancer─Design, Synthesis, and In Vitro Evaluation

Nada,

Gul,

Elkamhawy

et al. 2023

ACS Omega

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The epidermal growth factor receptor (EGFR) is vital for regulating cellular functions, including cell division, migration, survival, apoptosis, angiogenesis, and cancer. EGFR overexpression is an ideal target for anticancer drug development as it is absent from normal tissues, marking it as tumor-specific. Unfortunately, the development of medication resistance limits the therapeutic efficacy of the currently approved EGFR inhibitors, indicating the need for further development. Herein, a machine learning-based application that predicts the bioactivity of novel EGFR inhibitors is presented. Clustering of the EGFR smallmolecule inhibitor (∼9000 compounds) library showed that Nsubstituted quinazolin-4-amine-based compounds made up the largest cluster of EGFR inhibitors (∼2500 compounds). Taking advantage of this finding, rational drug design was used to design a novel series of 4-anilinoquinazoline-based EGFR inhibitors, which were first tested by the developed artificial intelligence application, and only the compounds which were predicted to be active were then chosen to be synthesized. This led to the synthesis of 18 novel compounds, which were subsequently evaluated for cytotoxicity and EGFR inhibitory activity. Among the tested compounds, compound 9 demonstrated the most potent antiproliferative activity, with 2.50 and 1.96 μM activity over MCF-7 and MDA-MB-231 cancer cell lines, respectively. Moreover, compound 9 displayed an EGFR inhibitory activity of 2.53 nM and promising apoptotic results, marking it a potential candidate for breast cancer therapy.

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Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies

Cited by 8 publications

References 60 publications

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library

Chalcone‐based benzenesulfonamides as potent and selective inhibitors for human carbonic anhydrase II: Design, synthesis, in vitro, and in silico studies

Machine Learning-Based Approach to Developing Potent EGFR Inhibitors for Breast Cancer─Design, Synthesis, and In Vitro Evaluation

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