Investigation of the Novel Lead of Melanocortin 1 Receptor for Pigmentary Disorders
Investigation of the Novel Lead of Melanocortin 1 Receptor for Pigmentary Disorders
Hsin-Chieh Tang1 and Calvin Yu-Chian Chen2,3,4,5
1Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan
2Department of Medicine, China Medical University, Taichung 40402, Taiwan
3Department of Biotechnology, Asia University, Taichung 41354, Taiwan
4China Medical University Beigang Hospital, Yunlin 65152, Taiwan
5Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Received 18 November 2013; Revised 15 December 2013; Accepted 15 December 2013; Published 17 February 2014
Academic Editor: Fuu-Jen Tsai
Copyright © 2014 Hsin-Chieh Tang and Calvin Yu-Chian Chen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Knowing the role of MC1R in skin tanning can provide a brand new idea to resolve pigmentary disorders. αMSH has 13 amino acids and is the most essential pigmentary melanocortin responsible for melanin synthesis. One could utilize the compound library to find lead compounds by virtual screening from peptide database and traditional Chinese medicine (TCM) database@Taiwan. Computational simulation provided a convenient technology to survey potential lead. Ligand-based validation set up the reliable model for molecular dynamics simulation. Molecular dynamics simulation approved the binding affinity and stability of the peptides selected by virtual screening. Thus, we concluded that Glu-Glu-Lys-Glu (EEKE), Glu-Gly-Gly-Ser-Val-Glu-Ser (EGGSVES), and Glu-Glu-Asp-Cys-Lys (EEDCK) were potent lead peptides for MC1R to resolve pigmentary disorders.
1. Introduction
Excessive melanin contributes to skin tanning or darkening. Ultraviolet (UV) radiation leads to skin pigmentation by manufacturing melanin in the melanocytes located at the basal layer of epidermis. Expression of the pro-opiomelanocortin (POMC) gene producing α-melanocyte stimulating hormone (αMSH) takes place in keratinocytes. αMSH recognizing melanocortin 1 receptor (MC1R) located on the cell membrane of melanocytes starts a series of signal pathways [1]. The αMSH/MC1R triggers downstream signal transduction which is followed by cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP responsive element binding protein/cAMP responsive element (CREB/CRE) pathway [2]. Microphthalmia-associated transcription factor (MITF) begins its function in turn. It is an important protein that controls the activation of following melanotic genes: tyrosinase and tyrosinase related protein 1 and 2 (Trp1 and Trp2) [3, 4].
MSHs belong to the POMC hormone groups and include three types of α, β, and γ-MSH [5]. Generally speaking, αMSH is a pituitary peptide hormone derived from adrenocorticotropic hormone (ACTH) [6]. αMSH which affects skin pigmentation mainly produces locally instead of pituitary origin [7].αMSH has 13 amino acids and is the most essential pigmentary melanocortin responsible for melanin synthesis or melanogenesis [8]. Its amino acid sequences are Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val [9]. Synthetic analogs of αMSH have been developed as useful probes binding to the melanocortin receptor or MC1R which is overexpressed in melanoma lesions [10, 11]. His6-Phe7-Arg8-Trp9 (HFRW) is the most common active motif approved in the literature [12, 13]. Experimental order exchange of αMSH had been demonstrated as high-affinity peptides binding to the MC1R but loss of their agonistic function [14].
Melanocortin receptors belong to class A or rhodopsin of the superfamily of 7-transmembrane G protein-coupled receptors (GPCRs) [15–17]. GPCR receives external signal, for example, hormones and neurotransmitters, vary in molecular size from small peptides to large proteins [18]. There are five known melanocortin receptors, MC1~5R [19]. They have similar structure conformation but participate in unique physiologic functions: pigmentation, adrenal function, cardiovascular regulation, obesity or energy homeostasis, and exocrine gland secretion [20, 21]. MC1R is the irreplaceable target involved in regulating our skin or hair color [22]. The coat color of animals or plumage color of birds is also regulated by MC1R gene [23, 24]. MC1R has 318 amino acids; αMSH is its agonist, and agouti signal protein is its antagonist. They determine the phenotype of our skin and hair by producing black, brown eumelanin or yellow, red pheomelanin [25].
Protein sequence and structure analysis by computational simulation have become popular technology in recent decades [26, 27]. We use computational systems biology or in silico biology to research the protein-molecule or the protein-ligand interaction [28, 29]. Drug discovery integrates systems biology and informatics called computer-aided drug design (CADD) [30, 31]. The advantages of CAD (...truncated)