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.
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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
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The authors are thankful to Nirma University, Ahmedabad, India, for providing the needful facilities to carry out research work.
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Chavda, J., Bhatt, H. 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. Struct Chem 30, 2093–2107 (2019). https://doi.org/10.1007/s11224-019-01334-9
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DOI: https://doi.org/10.1007/s11224-019-01334-9