RATIONAL DRUG DESIGN OF POTENT V600E-BRAF KINASE INHIBITORS THROUGH MOLECULAR DOCKING SIMULATION

Bello Abdullahi Umar; Adamu Uzairu; Gideion Adamu Shallangwa; Sani Uba

doi:10.18540/jcecvl5iss5pp0469-0481

Autores/as

Bello Abdullahi Umar
Adamu Uzairu
Gideion Adamu Shallangwa
Sani Uba

DOI:

https://doi.org/10.18540/jcecvl5iss5pp0469-0481

Palabras clave:

Melanoma, Quinolinylaminopyrimidines, binding energy, Pi–Pi interaction, V600E-BRAF

Resumen

B-RAF is a one of the RAF protein kinase group that contribute to the development of different types of cancer. V600E-BRAF protein has lot potential for scientific investigation as the therapeutic target owing to its participation in melanoma cancer and is the molecular target of many anticancer compounds like quinolinylaminopyrimidines (QAP) derivatives. In this research, interactions of QAP derivatives with V600E-BRAF kinase were modeled and predicted using molecular docking simulation approach with the help of Autodock vina version 4.0 of Pyrx software. The molecular docking simulation result of this research shows that QAP6 (?11.7 kcalmol^-1) best inhibit V600E-BRAF when compared with other QAP analogous within the dataset and was found to be better than the standard V600E-BRAF inhibitor vemurafenib (-11.3 kcalmol^-1). This compound (QAP6) were further used in designing novel and potent V600E-BRAF inhibitors by attaching substituents to the quinoline ring of the compound. Moreover, the two newly designed inhibitors N1 and N2 with a binding energy of ?12.7 kcalmol^-1 and –12.9 kcalmol^-1 respectively were found to be more potent than the parent structure QAP6 (?11.7 kcalmol^-1) and the standard V600E-BRAF inhibitor vemurafenib (-11.3 kcalmol^-1). Thus; this study provides a valuable approach and new direction to novel drug discovery. There is hope in the future studies to include the synthesis and evaluation of these newly designed inhibitors which can establish them to be the most potent V600E-BRAF inhibitors and efficient ant-melanoma cancer drug.

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BOLLAG, G., HIRTH, P., TSAI, J., ZHANG, J., IBRAHIM, P. N., CHO, H., SPEVAK, W., ZHANG, C., ZHANG, Y. & HABETS, G. 2010. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 467, 596.

BROSE, M. S., VOLPE, P., FELDMAN, M., KUMAR, M., RISHI, I., GERRERO, R., EINHORN, E., HERLYN, M., MINNA, J. & NICHOLSON, A. 2002. BRAF and RAS mutations in human lung cancer and melanoma. Cancer research, 62, 6997-7000.

CHOI, W.-K., EL-GAMAL, M. I., CHOI, H. S., BAEK, D. & OH, C.-H. 2011. New diarylureas and diarylamides containing 1, 3, 4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies. European journal of medicinal chemistry, 46, 5754-5762.

CUMMINS, D. L., CUMMINS, J. M., PANTLE, H., SILVERMAN, M. A., LEONARD, A. L. & CHANMUGAM, A. Cutaneous malignant melanoma. Mayo clinic proceedings, 2006. Elsevier, 500-507.

DHILLON, A. S., HAGAN, S., RATH, O. & KOLCH, W. 2007. MAP kinase signalling pathways in cancer. Oncogene, 26, 3279.

HEHRE, W. & HUANG, W. 1995. Chemistry with computation: an introduction to SPARTAN: Wavefunction. Inc, Irvine Google Scholar.

JEMAL, A., SIEGEL, R., WARD, E., MURRAY, T., XU, J., SMIGAL, C. & THUN, M. J. 2006. Cancer statistics, 2006. CA: a cancer journal for clinicians, 56, 106-130.

LEE, J. A., ROH, E. J., OH, C.-H., LEE, S. H., SIM, T., KIM, J. S. & YOO, K. H. 2015. Synthesis of quinolinylaminopyrimidines and quinazolinylmethylaminopyrimidines with antiproliferative activity against melanoma cell line. Journal of enzyme inhibition and medicinal chemistry, 30, 607-614.

LI, Z., JIANG, J.-D. & KONG, W.-J. 2014. Berberine up-regulates hepatic low-density lipoprotein receptor through Ras-independent but AMP-activated protein kinase-dependent Raf-1 activation. Biological and Pharmaceutical Bulletin, 37, 1766-1775.

LIPINSKI, C. A., LOMBARDO, F., DOMINY, B. W. & FEENEY, P. J. 2012. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 64, 4-17.

NAMBA, H., NAKASHIMA, M., HAYASHI, T., HAYASHIDA, N., MAEDA, S., ROGOUNOVITCH, T. I., OHTSURU, A., SAENKO, V. A., KANEMATSU, T. & YAMASHITA, S. 2003. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. The Journal of Clinical Endocrinology & Metabolism, 88, 4393-4397.

PUZANOV, I., AMARAVADI, R. K., MCARTHUR, G. A., FLAHERTY, K. T., CHAPMAN, P. B., SOSMAN, J. A., RIBAS, A., SHACKLETON, M., HWU, P. & CHMIELOWSKI, B. 2015. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression. European journal of cancer, 51, 1435-1443.

REN, L., WENGLOWSKY, S., MIKNIS, G., RAST, B., BUCKMELTER, A. J., ELY, R. J., SCHLACHTER, S., LAIRD, E. R., RANDOLPH, N. & CALLEJO, M. 2011. Non-oxime inhibitors of B-Raf V600E kinase. Bioorganic & medicinal chemistry letters, 21, 1243-1247.

ROBINSON, S. D., O'SHAUGHNESSY, J. A., COWEY, C. L. & KONDURI, K. 2014. BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib. Lung cancer, 85, 326-330.

ROSKOSKI, R. 2012. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochemical and biophysical research communications, 417, 5-10.

SAINI, K. S., LOI, S., DE AZAMBUJA, E., METZGER-FILHO, O., SAINI, M. L., IGNATIADIS, M., DANCEY, J. E. & PICCART-GEBHART, M. J. 2013. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer treatment reviews, 39, 935-946.

SHI, J.-H., CHEN, J., WANG, J., ZHU, Y.-Y. & WANG, Q. 2015. Binding interaction of sorafenib with bovine serum albumin: Spectroscopic methodologies and molecular docking. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 149, 630-637.

VISWANADHAN, V. N., GHOSE, A. K., REVANKAR, G. R. & ROBINS, R. K. 1989. Atomic physicochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. Journal of chemical information and computer sciences, 29, 163-172.

WANG, L., BERNE, B. & FRIESNER, R. 2011. Ligand binding to protein-binding pockets with wet and dry regions. Proceedings of the National Academy of Sciences, 108, 1326-1330.

WU, C.-P. & AMBUDKAR, S. V. 2014. The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy. Acta Pharmaceutica Sinica B, 4, 105-111.

ZUBRILOV, I., SAGI-ASSIF, O., IZRAELY, S., MESHEL, T., BEN-MENAHEM, S., GINAT, R., PASMANIK-CHOR, M., NAHMIAS, C., COURAUD, P.-O. & HOON, D. S. 2015. Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells. Cancer letters, 361, 86-96.