In silico ADME/T and 3D QSAR analysis of KDR inhibitors

Hosen, S. M. Zahid; Dash, Raju; Khatun, Mahbuba; Akter, Rasheda; Bhuiyan, Md. Hr; Karim, Md. Rezaul; Mouri, Nusrat Jahan; Ahamed, Forkan; Islam, Kazi S; Afrin, Sadia

doi:10.7324/japs.2017.70116

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…In this study, the predicted plasma-protein binding has been estimated by the QPlog KHSA; the prediction of binding to human serum albumin. [24] With the exception of compound β-sitosterol, all compounds had values that were within the standard range of drug-like compounds. This might be attributed to the hydrophobic nature of the compound which contributed to its strong binding affinity to plasma proteins.…”

Section: Prediction Of Plasma-protein Binding (Distribution)mentioning

confidence: 91%

Chemical Constituents from Artemisia annua and Vitex agnus-castus as New Aromatase Inhibitors: In-vitro and In-silico Studies

et al. 2020

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Abstract. Aromatase inhibitors are important in certain cancers such as breast cancer in postmenopausal women. In this study, eight constituents from Artemisia annua L. and Vitex agnus-castus L. were isolated and evaluated for their aromatase inhibitory activity using in-vitro fluorimetric assay. All tested compounds possessed moderate to strong inhibitory activity with β-sitosterol and myricetin-3,7,4'-trimethyl ether being the most active with IC50 values of 0.13 and 0.25 μM, respectively. Compounds were subjected to induced fit docking (IFD) where β-sitosterol, possessed comparable interaction patterns to the natural co-crystallized ligand androstenedione. Furthermore, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME&T)‎ properties of the compounds were evaluated revealing that all compounds' properties - except some of β- sitosterol related to solubility - lied within the acceptable range for human use, thereby considered as competent drug-like molecules. These findings could qualify β- sitosterol, myricetin-3,7,4'-trimethyl ether and domesticoside as lead compounds for the development of new aromatase inhibitors.

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Section: Prediction Of Plasma-protein Binding (Distribution)mentioning

confidence: 91%

Chemical Constituents from Artemisia annua and Vitex agnus-castus as New Aromatase Inhibitors: In-vitro and In-silico Studies

et al. 2020

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“…All designed compounds have higher bioavailability score of 0.55 except compounds 9, 13, and 14 with lower bioavailability scores of 0.17. Interestingly, all the designed compounds have a good synthetic accessibility score of < 5 except molecule 9 with the synthetic accessibility score > 5 (5.16) which indicates that these designed compounds can be easily synthesized in the laboratory [25,27].…”

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

confidence: 99%

“…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%

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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“…Form the Table, None of the designed compounds was found to violate more than the permissible limit set by the Lipinski's rule of five filters. And therefore predicting their easy transportation, absorption and diffusion [23]. ADME properties of these designed compounds were also predicted as shown in Table 8.…”

Section: Drug-likeness and Adme Properties Of Designed Nsclc Therapeumentioning

confidence: 99%

“…All designed compounds have lower bioavailability score of 0.17 except compound 3 and 4. Based on their synthetic accessibility scores, they can easily be synthesized in the laboratory [23].…”

Section: Drug-likeness and Adme Properties Of Designed Nsclc Therapeumentioning

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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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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In silico ADME/T and 3D QSAR analysis of KDR inhibitors

Cited by 16 publications

References 15 publications

Chemical Constituents from Artemisia annua and Vitex agnus-castus as New Aromatase Inhibitors: In-vitro and In-silico Studies

Chemical Constituents from Artemisia annua and Vitex agnus-castus as New Aromatase Inhibitors: In-vitro and In-silico Studies

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

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

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