3D‐QSAR and Molecular Docking Studies on Substituted Isothiazole Analogs as Inhibitors Against MEK‐1 Kinase

Abstract

Both authors made equal contribution to the work.MEK-1 and MEK-2 are dual-specificity kinases and important components in the mitogen-activated protein kinase pathway. These enzymes are crucial for normal cell survival and are also expressed in several types of cancers, making them important targets for drug design. We have applied an integrated in silico approach that combines comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular docking to study the structural determinants for the recognition of substituted isothiazole analogs as allosteric inhibitors against MEK-1 kinase. The best 3D-QSAR models for comparative molecular field analysis and comparative molecular similarity indices analysis were selected based on statistical parameters. 3D contour maps suggested that bulky or long-chain substitutions at the X position on the core part decrease the inhibitory activity, and the presence of a hydrogen bond donor substitution enhances the activity. The bulky and electronegative substitutions at the Y position on the core part enhance the activity of the inhibitors. Molecular docking studies reveal a large and hydrophobic pocket that accommodates the Y substitution and a polar pocket that accommodates substitutions on the X position and forms hydrogen bonding interactions with MEK-1 kinase. The results of the 3D-QSAR analysis corroborate with the molecular docking results, and our findings will serve as a basis for further development of better allosteric inhibitors of MEK-1 kinase against several cancers.Key words: allosteric inhibitor, comparative molecular field analysis, comparative molecular similarity indices analysis, MEK-1 kinase, molecular docking, substituted isothiazole analogs, three-dimensional quantitative structure-activity relationship In eukaryotes, signals from outside the cell to inside the nucleus are transduced by various growth factors, hormones, adaptor proteins, and enzymes to regulate normal cell survival, proliferation, and differentiation. The mitogen-activated protein kinase (MAPK) pathway that includes the Ras ⁄ Raf ⁄ MEK ⁄ extracellular-signal regulated kinase (ERK) signaling proteins is one of the important pathways in signal transduction. Ras is an upstream activator of several signaling pathways such as MAPK pathway. Kinase suppressor of Ras is an essential scaffolding protein that co-ordinates the assembly of Raf-MEK-ERK complexes (1-3). B-Raf and other upstream activator kinases phosphorylate and activate the MAP kinase ⁄ ERK kinases (MEK-1 and MEK-2) via serine phosphorylation. The activated MEK-1 and MEK-2 phosphorylate and activate the ERK1 and ERK2 MAPKs. MEK-1 and MEK-2 are dual specificity kinases that phosporylate both threonine and tyrosine residues on ERK1 and ERK2 (43-and 41-kDa MAP kinases, respectively) (4-6). In tumor cells, aberrant activation of the MAPK pathway owing to the mutations in Ras and Raf is frequently observed. Also, activated MAPK or elevated MAPK expression has been detected in a variety of human tumors, ...

The N’-Substituted Derivatives of 5-Chloro-3-Methylisothiazole-4-Carboxylic Acid Hydrazide with Antiproliferative Activity

“…In addition, the compounds with this structure may exist as cis-trans amide conformers [26][27][28]. What is more, we have done 1 H- 13 C NMR correlations ( Figures S41-S50) for all compounds, which confirmed the presence of isomers. The correlation spectrum of the proton and carbon in the most active compound 3 ( Figure 1) allows us to determine the presence of double signals from geometric isomers.…”

“…In the present study, the spectral data were measured in a DMSO-d 6 solution. For these compounds, we observed in 1 H-NMR and 13 C-NMR signals belonging to Z and E geometrical isomers about the C=N double bond, which is characteristic of arylidene-hydrazide structure [21][22][23][24][25]. In addition, the compounds with this structure may exist as cis-trans amide conformers [26][27][28].…”

“…The structures of new compounds were also determined by mass spectrometry ( Figures S1-S10). In the 1 H-NMR (Figures S11-S30) and 13 C-NMR ( Figure S31-S40) spectra, double signals for each of the protons were present.…”

“…The samples were applied as solids and frequencies are given in cm −1 . Proton nuclear magnetic resonance ( 1 H-NMR), carbon nuclear magnetic resonance ( 13 C-NMR) and 2D 1 H- 13 C NMR correlation spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d 6 ) using a Bruker ARX-300 spectrometer (Bruker Analytische Messtechnik GmbH, Rheinstetten, Germany). Chemical shifts are reported in in parts per million (ppm) units and signal multiplicities were collected by the abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet).…”

“…Another biological target of various isothiazole derivatives are MEK1 and MEK2 kinases [11][12][13][14], checkpoint kinases (Chk1 and Chk2) [15,16], tropomyosin receptor kinase A, TrkA [17] and a histone acetyltransferase (HAT enzyme)-Tip60 (KAT5) [18], whose overexpression is responsible for the induction of malignancy. This is a direction of intensive research, which addresses the synthesis of new isothiazole derivatives with the activity of tumor suppression inhibitors.…”