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Pharmacophore, 3D-QSAR models and Dynamic Simulation of 1,4-Benzothiazines for Colorectal Cancer Treatment

Author(s):

Amit Rai, Vinit Raj, Mohamed Hodhod Aboumanei, Ashok K Singh, Amit K Keshari, Suraj P.Verma and Sudipta Saha  

Abstract:


Interleukin-6 has become an attractive protein target. This is found in the progression of colon cancer. It performs various functions in the colon cancer cells such as inflammation, activates various cell types signaling and also promotes proliferation in colon cancer cells. It is a valid target to develop of anticolon cancer drug. The purpose of our study is to develop the Three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models, pharmacophore modeling and docking study as well as MD simulation to find out the novel potent inhibitors that bind with Interleukin-6 in colon cancer treatment. In this study, common pharmacophore models and atom-based 3D-QSAR studies were carried out by using 1,4-benzothiazine derivatives with their experiential GI50 values towards HT-29 human colon cancer cell line. The common pharmacophore model (ADHR26) was developed and the survival score was found to be 3.617. The generated pharmacophore-based alignment was used to develop a predictive atom-based 3D-QSAR model by using Partial Least Square (PLS) method. Phase predictable activity and LogGI50 also exhibited the most significant atomic position in the backbone structure of ligands for anticolon cancer activity. Molecular dynamic and docking studies for the IL-6 target provide key framework of ligand for the anticolon cancer activity. Finally, results generated from the work data, that exhibited the pharmacophore models and 3D-QSAR hypothesis might be a path of milestone in the area of medicinal chemistry to researchers for further design of new and potent IL-6 inhibitors.

Keywords:

1, 4-benzothiazine, Pharmacophore modeling, 3D-QSAR, Interleukin-6, Colon cancer, Docking study and Molecular dynamic simulation.

Affiliation:

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, Egyptian Atomic Energy Authority, Cairo 11371 , Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, Department of Pharmaceutical Sciences, Kumaun University, Bhimtal Campus, Nainital Uttarakand, Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025



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