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Structural Chemistry

, Volume 30, Issue 6, pp 2093–2107 | Cite as

3D-QSAR (CoMFA, CoMSIA, HQSAR and topomer CoMFA), MD simulations and molecular docking studies on purinylpyridine derivatives as B-Raf inhibitors for the treatment of melanoma cancer

  • Jaydeepsinh Chavda
  • Hardik BhattEmail author
Original Research
  • 33 Downloads

Abstract

As per the World Health Organization (WHO), cancer is the second most leading cause of death after cardiovascular diseases in worldwide with around 9.88 million total new cases and 1.08 million were observed due to skin cancer in 2018. Amongst two types of skin cancer, progression of melanoma cancer is increasing day by day due to the environmental changes than non-melanoma cancer. Most of B-Raf mutation, specifically B-RafV600E, is responsible for the progression of the melanoma cancer. Here, various 3D-QSAR techniques like comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular hologram QSAR (HQSAR) and topomer CoMFA were used to design novel B-Raf inhibitors by using 28 synthetic B-Raf inhibitors. Except for topomer CoMFA model, remaining models were generated by three different alignment methods in which distil-based alignment method was found best and gave prominent statistical values. After performing N-fold statistical validation, in CoMFA, q2, r2 and r2pred values were found to be 0.638, 0.969 and 0.848, respectively. Similarly, q2, r2 and r2pred values were found to be 0.796, 0.978 and 0.891 in CoMSIA (SHD) and 0.761, 0.973 and 0.852 in CoMSIA (SH) by N-fold statistical validation. In HQSAR analysis, statistical values were found for q2 as 0.984, r2 as 0.999 and r2pred as 0.634 with 97 as best hologram length (BHL). The results of topomer CoMFA showed the q2 value of 0.663 and the r2 value of 0.967. Important features of purinylpyridine were identified by contour map analysis of all 3D-QSAR techniques, which could be useful to design the novel molecules as B-Raf inhibitors for the treatment of melanoma cancer.

Keywords

Melanoma B-Raf Purinylpyridine 3D-QSAR MD/MS 

Abbreviations

Raf

Rapidly accelerated fibrosarcoma

RAS

Retrovirus-associated DNA sequences

MAPK

Mitogen-activated protein kinase

RTK

Receptor tyrosine kinase

ERK

Extracellular regulated kinase

3D-QSAR

Three-dimensional quantitative structural activity relationship

CoMFA

Comparative molecular field analysis

CoMSIA

Comparative molecular similarity indices analysis

HQSAR

Molecular hologram QSAR

MD/MS

Molecular docking and molecular simulation

Notes

Acknowledgements

The authors are thankful to Nirma University, Ahmedabad, India, for providing the needful facilities to carry out research work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11224_2019_1334_MOESM1_ESM.docx (242 kb)
ESM 1 (DOCX 241 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Institute of PharmacyNirma UniversityAhmedabadIndia

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