Design of a new class of superpotent cyclic α-melanotropins based on quenched dynamic simulations

Fahad Al-Obeidi, Mac E. Hadley, B. Montgomery Pettitt, Bernard Pettitt

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

A new highly potent, receptor-selective and prolonged-acting cyclic lactam analogue of α-melanotropin (α-MSH) has been designed and synthesized. Molecular dynamics simulations and molecular mechanics calculations were used in conjunction with results from previous conformational structure-biological activity studies to design a new class of linear and cyclic α-melanotropin (α-MSH) analogues. Examination of these properties of α-MSH and [Nle4,D-Phe7]α-MSH led to the design of the potent linear fragment analogue Ac-[Nle4,Asp5,D-Phe7,Lys 10]α-MSH4-10-NH2, in which the Gly10 residue of α-MSH4-10 was replaced by Lys10 as the major novel change from previous investigations. This in turn led to the synthesis of the cyclic lactam analogue Ac-[Nle4,Asp5,D-Phe7,Lys 10]α-MSH4-10-NH2, which was exceptionally potent in the lizard skin (90 times that of α-MSH) and mammalian melanoma tyrosinase (100 times that of α-MSH) assays and in addition exhibited prolonged biological activity.

Original languageEnglish (US)
Pages (from-to)3413-3416
Number of pages4
JournalJournal of the American Chemical Society
Volume111
Issue number9
StatePublished - 1989
Externally publishedYes

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Melanocyte-Stimulating Hormones
Bioactivity
Molecular mechanics
Computer simulation
Molecular dynamics
Assays
Skin
Lactams
Lizards
Monophenol Monooxygenase
Molecular Dynamics Simulation
Mechanics
Melanoma

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Design of a new class of superpotent cyclic α-melanotropins based on quenched dynamic simulations. / Al-Obeidi, Fahad; Hadley, Mac E.; Pettitt, B. Montgomery; Pettitt, Bernard.

In: Journal of the American Chemical Society, Vol. 111, No. 9, 1989, p. 3413-3416.

Research output: Contribution to journalArticle

Al-Obeidi, Fahad ; Hadley, Mac E. ; Pettitt, B. Montgomery ; Pettitt, Bernard. / Design of a new class of superpotent cyclic α-melanotropins based on quenched dynamic simulations. In: Journal of the American Chemical Society. 1989 ; Vol. 111, No. 9. pp. 3413-3416.
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