Insilico study of anti-carcinogenic lysyl oxidase-like 2 inhibitors

Muhammad, Syed Aun; Ali, Amjad; Ismail, Tariq; Zafar, Rehan; Ilyas, Umair; Ahmad, Jamil

doi:10.1016/j.compbiolchem.2014.03.002

Cited by 11 publications

(5 citation statements)

References 24 publications

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“…Considering hydrophobic properties of these interacting molecules (ACE protein target and quercetin) using the concepts of the molecular hydrophobicity potential was calculated. [ 20 ] These hydrophobicity maps are used to analyze the progress of hydrophobicity clusters on the membrane surface along the molecular dynamics run and the features of interface between the membrane and membrane-binding molecule [ Figure 3 ].…”

Section: Resultsmentioning

confidence: 99%

In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

Muhammad

Fatima

2015

Phcog Mag

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The purpose of this study was to analyze the inhibitory action of quercetin glycosides by computational docking studies. For this, natural metabolite quercetin glycosides isolated from buckwheat and onions were used as ligand for molecular interaction. The crystallographic structure of molecular target angiotensin-converting enzyme (ACE) (peptidyl-dipeptidase A) was obtained from PDB database (PDB ID: 1O86). Enalapril, a well-known brand of ACE inhibitor was taken as the standard for comparative analysis. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. The quercetin showed optimum binding affinity with a molecular target (angiotensin-converting-enzyme) with the binding energy of −8.5 kcal/mol as compared to the standard (−7.0 kcal/mol). These results indicated that quercetin glycosides could be one of the potential ligands to treat hypertension, myocardial infarction, and congestive heart failure.

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Section: Resultsmentioning

confidence: 99%

In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

Muhammad

Fatima

2015

Phcog Mag

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“…Muhammad and colleagues designed two triazole derivatives ( Figure ) which have promising Δ G binding affinity to LOXL2 using in silico methods (−6.2 to −8.9 kcal mol −1 ) . Both compounds had a stabilized interaction with the active site of LOXL2 via the formation of hydrogen bonds and π‐stacking interactions.…”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

“…Both compounds had a stabilized interaction with the active site of LOXL2 via the formation of hydrogen bonds and π‐stacking interactions. Unfortunately, the crystal structure of LOXL2 was not published at the time of publication and therefore a predicted model of LOXL2 was used in this study . No biological testing to confirm the in silico results was reported.…”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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“…In silico designing has been used for different proteins( 33 34 35 ). In this regard, we applied this approach for site specific PEGylation, a well-known method used to prolong the circulating half-lives of protein therapeutics and to improve both their stability and efficiency( 36 37 38 ).…”

Section: Discussionmentioning

confidence: 99%

In silico designing of a new cysteine analogue of hirudin variant 3 for site specific PEGylation

et al. 2017

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Hirudin is an anticoagulant agent of the salivary glands of the medicinal leech. Recombinant hirudin (r-Hir) displays certain drawbacks including bleeding and immunogenicity. To solve these problems, cysteine-specific PEGylation has been proposed as a successful technique. However, proper selection of the appropriate cysteine residue for substitution is a critical step. This study has, for the first time, used a computational approach aimed at identifying a single potential PEGylation site for replacement by cysteine residue in the hirudin variant 3 (HV3). Homology modeling (HM) was performed using MODELLER. All non-cysteine residues of the HV3 were replaced with the cysteine. The best model was selected based on the results of discrete optimized protein energy score, PROCHECK software, and Verify3D. The receptor binding was investigated using protein-protein docking by ClusPro web tool which was then visualized using LigPlot+ software and PyMOL. Finally, multiple sequence alignment (MSA) using ClustalW software and disulfide bond prediction were performed. According to the results of HM and docking, Q33C, which was located on the surface of the protein, was the best site for PEGylation. Furthermore, MSA showed that Q33 was not a conserved residue and LigPlot+ software showed that it is not involved in the hirudin-thrombin binding pocket. Moreover, prediction softwares established that it is not involved in disulfide bond formation. In this study, for the first time, the utility of the in silico approach for creating a cysteine analogue of HV3 was introduced. Our study demonstrated that the substitution of Q33 by cysteine probably has no effect on the biological activity of the HV3. However, experimental analyses are required to confirm the results.

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Insilico study of anti-carcinogenic lysyl oxidase-like 2 inhibitors

Cited by 11 publications

References 24 publications

In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

In silico designing of a new cysteine analogue of hirudin variant 3 for site specific PEGylation

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