Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR /Akt pathway inhibitors

Khan, Irfan; Garikapati, Koteswara Rao; Setti, Aravind; Shaik, Anver Basha; Makani, Venkata Krishna Kanth; Shareef, Mohd Adil; Rajpurohit, Hemshikha; Vangara, Namratha; Pal‐Bhadra, Manika; Kamal, Ähmed; Kumar, C. Ganesh

doi:10.1016/j.ejmech.2018.12.011

Cited by 42 publications

(18 citation statements)

References 43 publications

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“…A series of 7-amino- [1,2,4] triazolo [4,3-f] pteridinone, and 7-aminotetrazolo[1,5-f] pteridinone derivative (35 compounds) as NSCLC therapeutic agents were sourced from the literature and used in this work [15]. After the dataset were sourced, Chemdraw software version 12.0.1 was used to achieve the sketching of the 2D structures of all the dataset under consideration [16].…”

Section: Sourcing Sketching and Determination Of The Optimum Structumentioning

confidence: 99%

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Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

2020

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Purpose Cancer was recognised to be daunting illness and second cause of death worldwide. The death estimate caused by cancer as of 2012 was about 17% of the total deaths (which is about 8.5 million) and in 2030 will be about 13.1 million deaths. Lung cancer is one of the leading cancer problems in the globe. It was reported to cause a lot of death every year. In all types of cancer, non-small cell lung cell (NSCLC) is one of the various causes of cancer-related mortality. Therefore there is need to design more potent NSCLC therapeutic agents. The purpose of this work is to identify lead compounds among the investigated ant-cancer agents with prominent activity against NSCLC and also design new NSCLC therapeutic agents by carrying out structural modification on the best lead compound using Structure-based approach. Method The method employed in this research is structure-based drug design approach on some anti-cancer agents. It involves molecular docking which study how these anti-cancer agents interact in with active site of their target protein (EGFR receptor PDB code: 4ZAU) and identify which among the investigated molecules have the lowest docking score/ highest binding affinity toward the target and then predict their pharmacokinetic profile. The best among them will be used as template for designing new NSCLC therapeutic agents with higher affinity toward EGFR receptor. Result The investigation of the binding mode of some NSCLC therapeutic agents against EGFR receptor (PDB: 4ZAU) was achieved through docking in this research. Five compounds exhibited the best docking scores among the docked ligands were compound 7, 19, 22, 27 and 34. Compound 19 and 27 under investigation were found to have the lowest docking score of-9.7 kcal/mol among the compounds under investigation. Compound 19 was seen to interact in the binding site of EGFR receptor through electrostatic interaction with LYS745 amino acid residue of the EGFR receptor, hydrophobic interaction with LYS745, VAL726, ALA743, LEU844 and LEU718 amino acid residues and hydrogen bond interaction with GLU762 (2.69145 Å), ASP855 (2.78155 Å) and LYS745 (3.05463 Å) amino acid residues in the binding site of EGFR receptor which might be responsible for the lowest energy (highest docking score) of the ligand. The ADME/Pharmacokinetics and druglikeness of these lead compounds and compound 27 were predicted and observed to be orally bioavailable because none of them broke more than the allowable limit by Lipinski's RO5 filters. Compound 27 was retained and used as a template for the designing process. Thirteen (13) new NSCLC therapeutic agents were designed were designed by carrying out structural modification on methyl group attached to '1, 2, 4 triazolo pteridinone' moiety and two methyl groups attached to 'piperidin-1-yl' of the template. Conclusion The molecular docking simulation, ADME/Pharmacokinetics and drug-likeness employed on some NSCLC therapeutic agents discovered five compounds (7, 19, 22, 27 and 34) with the lowest docking scores among other compounds ...

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Section: Sourcing Sketching and Determination Of The Optimum Structumentioning

confidence: 99%

“…Cancer was recognised to be daunting illness and second cause of death globally. The death estimate caused by cancer as of 2012 was about 17% of the total deaths (which is about 8.5 million) and in 2030 will be about 13.1 million deaths [1]. Lung cancer is one of the leading cancer problems in the globe.…”

Section: Introductionmentioning

confidence: 99%

Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

2020

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“…Synthetic accessibility score of all the compounds under investigation including the three (3) hit compounds was less than 5 showing that they can be easily synthesized in the laboratory. The compounds under investigation including the three hit compounds were predicted to have good pharmacokinetic profile and drug-likeness except compound 16 [24,25].…”

Section: Drug-likeness and Adme Property Prediction Of The Studied Comentioning

confidence: 99%

“…None of the designed compounds was found to violate more than two of the permissible limit set by the Lipinski's rule of five filters for small molecules. Based on that, their permeability across the cell membrane, easy transportation, absorption, and diffusion was predicted [24,26].…”

Section: Drug-likeness and Adme Prediction Of The Newly Designed Compmentioning

confidence: 99%

Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

Ibrahim

Uzairu

Shallangwa

2020

Egypt J Med Hum Genet

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Background The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Result Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. Conclusion The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

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“…It also exhibited a very broad range of beneficial biological activities including antimicrobial (antibacterial, antifungal), anti‐inflammatory, anti‐parasitic (anti‐malarial, anti‐leishmanial), antioxidant, antimitotic, anti‐invasive, anti‐tuberculosis, anticancer, as well as modulation of P‐glycoprotein‐mediated multidrug resistance . Chalcones are regarded as promising anticancer agents by interacting with cellular targets like Nrf2/ARE, EGFR, ODC, proteasome, nuclear factor‐κB (NF‐κB)‐mediated defense mechanisms and also by its strong capability of inducing apoptosis . Similarly, it may be lacking important genotoxic side effects like amino group interaction of nucleic acids which was exhibited by a number of clinically useful anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

One‐Pot Synthesis and Biological Evaluation of Arylpropenone Aminochalcone Conjugates as Potential Apoptotic Inducers

et al. 2019

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A facile single pot strategy was developed to synthesize a library of 17 arylpropenone aminochalcone conjugates involving two consecutive reactions, namely Michael addition and Claisen‐Schmidt condensation. These conjugates were screened for their in vitro anti‐proliferative potential against selected human cancer cell lines such as breast (MCF‐7 and MDA‐MB‐231), pancreatic (PANC‐1) and colorectal (CaCO2) adenocarcinoma cells. Among them, the conjugates 6 l and 6p exhibited good to moderate cytotoxicity with IC50 values ranging from 6.7 μM and 9.8 μM, respectively, against MCF‐7. Furthermore, these conjugates were found to exhibit G0/G1 cell cycle arrest. Moreover, Annexin‐FITC assay revealed that they induced apoptosis in a dose‐dependent manner which probably is responsible for their Cytotoxicity

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Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR /Akt pathway inhibitors

Cited by 42 publications

References 43 publications

Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

One‐Pot Synthesis and Biological Evaluation of Arylpropenone Aminochalcone Conjugates as Potential Apoptotic Inducers

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