Crystal structure determination and computational studies of 1,4-dihydropyridine derivatives as selective T-type calcium channel blockers

Date

2021-04-01

Author

GÜNDÜZ, MİYASE GÖZDE
Armakovic, Sanja J.
Dengiz, Çağatay
Tahir, Muhammad Nawaz
Armakovic, Stevan

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

197
views

0
downloads

Different types of calcium channels are crucial regulators of many key physiological functions throughout the body. Therefore, calcium channel modulators are accepted as precious molecules for the therapeutic intervention of various pathologies ranging from cardiovascular to neurological diseases. 1,4-dihydropyridines (DHPs) primarily target L-type calcium channel (Ca(v)1.2) for the treatment of hypertension and occupy a central position among all calcium channel blockers. Subsequently, T-type calcium channel Ca(v)3.2 isoform has been established to play a significant role in chronic pain conditions. Despite the growing interest and identification of many compounds with Ca(v)3.2 blocking activities, no molecule has passed the clinical trials and approved for the treatment of pain by now. Our group has recently identified two DHP-based molecules (HM8 and MD20) that selectively blocked T-type over L-type calcium channel. As these compounds hold great therapeutic value as potential drug candidates, we carried out further structural and computational analyses to gain insights into their various properties. Initially, the three-dimensional structure of HM8 was resolved by single-crystal X-ray analysis. The computational analysis encompassed density functional theory (DFT) and molecular dynamics (MD) simulations. DFT calculations were used to identify local reactivity properties and pharmaceutical stability, while time-dependent DFT calculations were used to simulate the UV/Vis spectra and identify the molecular parts principally responsible for the light absorption. MD simulations were used to understand the influence of water on studied molecules, and also to identify the substances that could be potentially used as excipients in pharmaceutical formulations based on HM8 and MD20. (C) 2021 Elsevier B.V. All rights reserved.

URI

https://hdl.handle.net/11511/90151

Journal

JOURNAL OF MOLECULAR STRUCTURE

DOI

https://doi.org/10.1016/j.molstruc.2021.129898

Collections

Department of Chemistry, Article

Suggestions

OpenMETU
Core

Molecular recognition of poly(A) by small ligands: an alternative method of analysis reveals nanomolar, cooperative and shape-selective binding Persil Çetinkol, Özgül (Oxford University Press (OUP), 2009-02-01) A few drug-like molecules have recently been found to bind poly(A) and induce a stable secondary structure (T(m)approximate to 60 degrees C), even though this RNA homopolymer is single-stranded in the absence of a ligand. Here, we report results from experiments specifically designed to explore the association of small molecules with poly(A). We demonstrate that coralyne, the first small molecule discovered to bind poly(dA), binds with unexpectedly high affinity (K(a) >10(7) M(-1)), and that the crescent sh...
Protein-based materials in load-bearing tissue-engineering applications Sayin, Esen; Baran, Erkan Turker; Hasırcı, Vasıf Nejat (2014-01-01) Proteins such as collagen and elastin are robust molecules that constitute nanocomponents in the hierarchically organized ultrastructures of bone and tendon as well as in some of the soft tissues that have load-bearing functions. In the present paper, the macromolecular structure and function of the proteins are reviewed and the potential of mammalian and non-mammalian proteins in the engineering of load-bearing tissue substitutes are discussed. Chimeric proteins have become an important structural biomater...
Novel Fluorescent Azacyanine Compounds: Improved Synthesis and Optical Properties Doğan, Kübra; Forough, M; Persil Çetinkol, Özgül (2020-09-01) Benzothiazoles are known to possess a number of biological activities and therefore are considered to be an important scaffold in the design and synthesis of pharmacophores. In this study, an improved synthesis method for novel fluorescent benzothiazole-based cyclic azacyanine (CAC) dyes bearing different electron-donating/withdrawing groups on their scaffold is presented. The improved method enabled us to increase the synthesis yield for the previously reported CACs. More importantly, it allowed us to synt...
Oligomerization and cell surface expression of recombinant GABA(A) receptors tagged in the delta subunit Oflaz, Furkan Enes; Son, Çağdaş Devrim; Arslan, Ayla (IMR Press, 2019-12-01) The gamma-Aminobutyric acid type A receptors (GABA(A) Rs) are heteropentameric chloride channels responsible for primary inhibition in the mammalian brain. Studies have shown the expression of recombinant GABA(A) R subunits tagged with the green fluorescent protein (GFP), a 26.9 kDa protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. This allows the formation of recombinant proteins essential for the development of relevant in-vitro and in-vivo methodologi...
Protein-Protein Interactions in Live Cells: Reinventing the Wheel Son, Çağdaş Devrim (2018-12-13) G protein-coupled receptors (GPCRs) are membrane proteins that mediate physiologicalresponse to a diverse array of stimuli. In humans, they mediate the action of hundreds ofpeptide hormones, sensory stimuli, odorants, neurotransmitters, and chemokines. GPCRs alsoare targets for ~40% of all currently marketed pharmaceuticals. These receptors traditionallybeen thought to act as monomeric units. However, recent evidence suggests that GPCRs mayform dimers as part of their normal trafficking and function. While ...

Citation Formats

M. G. GÜNDÜZ, S. J. Armakovic, Ç. Dengiz, M. N. Tahir, and S. Armakovic, “Crystal structure determination and computational studies of 1,4-dihydropyridine derivatives as selective T-type calcium channel blockers,” JOURNAL OF MOLECULAR STRUCTURE, pp. 0–0, 2021, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/90151.