Quantum Chemistry Calculation-Aided Structural Optimization of Combretastatin A‑4-like Tubulin Polymerization Inhibitors: Improved Stability and Biological Activity

A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor <b>22b</b> was found with strong antitumor activity previously. However, it easily undergoes <i>cis–trans</i> isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of <b>22b</b> were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds <b>1</b> and <b>3b</b> displayed more potent inhibitory activity on tumor cell growth than <b>22b</b>. In addition, the potent <i>in vivo</i> antitumor activity of compound <b>1</b> was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors

Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1

<div><p>Protein arginine methyltransferase 1 (PRMT1), the major arginine asymmetric dimethylation enzyme in mammals, is emerging as a potential drug target for cancer and cardiovascular disease. Understanding the catalytic mechanism of PRMT1 will facilitate inhibitor design. However, detailed mechanisms of the methyl transfer process and substrate deprotonation of PRMT1 remain unclear. In this study, we present a theoretical study on PRMT1 catalyzed arginine dimethylation by employing molecular dynamics (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) calculation. Ternary complex models, composed of PRMT1, peptide substrate, and S-adenosyl-methionine (AdoMet) as cofactor, were constructed and verified by 30-ns MD simulation. The snapshots selected from the MD trajectory were applied for the QM/MM calculation. The typical S_N2-favored transition states of the first and second methyl transfers were identified from the potential energy profile. Deprotonation of substrate arginine occurs immediately after methyl transfer, and the carboxylate group of E144 acts as proton acceptor. Furthermore, natural bond orbital analysis and electrostatic potential calculation showed that E144 facilitates the charge redistribution during the reaction and reduces the energy barrier. In this study, we propose the detailed mechanism of PRMT1-catalyzed asymmetric dimethylation, which increases insight on the small-molecule effectors design, and enables further investigations into the physiological function of this family. </p> </div

The overall structure of PRMT1-RGG-AdoMet complex and Atoms involved in QM region.

<p>Overall structure of (A) the PRMT1-RGG-AdoMet complex and (B) the microenvironment in active site. Atoms involved in the QM region (stick), and the structure parameters of the PRMT1-RGG-AdoMet complex (C) and the PRMT1-meRGG-AdoMet complex (D).</p

Potent Antitumor Activities and Structure Basis of the Chiral β‑Lactam Bridged Analogue of Combretastatin A‑4 Binding to Tubulin

A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound <b>9</b> was determined by X-ray crystallography, which showed that <b>9</b> binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities

Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound <b>17</b> (IC₅₀ = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of <b>17</b> to PRMT5 was validated by surface plasmon resonance experiments, with a <i>K_d</i> of 0.987 μM. Kinetic experiments indicated that <b>17</b> was a SAM competitive inhibitor other than the substrate. In addition, <b>17</b> showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. <b>17</b> may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications

Evolution of the Wiberg bond order during the first methyl transfer.

<p>(A) Illustration of the bond and atom name. (B) The relationship between the formation of OE2-2HH2 and CE-NH2 suggests that deprotonation occurs after methyl transfer. (C) The bond order evolution involved in the guanidino group indicates the charge redistribution during reaction (R: Reactant, TS: S_N2 transition state, P: product)..</p

Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

<p>A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor <b>ZJ01</b> was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. <b>ZJ01</b> could <i>in vitro</i> trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, <b>ZJ01</b> suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells. Moreover, in an <i>in vivo</i> mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, <b>ZJ01</b> demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound <b>ZJ01</b> is a promising drug lead for septic cardiomyopathy treatment.</p> <p><b>ZJ01</b> was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by <i>in vitro</i> and <i>in vivo</i> experiments.</p

Proposed PRMT1 Catalytic Mechanism.

<p>Proposed PRMT1 Catalytic Mechanism.</p

Potential Energy Surface of the first (A) and second (B) methyl transfer.

<p>Only the states adjacent to TS were included in the contour plot. Structure of the reactant (R), S_N2 transition state (TS), and product (P) in the first (C) and second (D) methyl transfers.</p

Evolution of electrostatic potential (ESP) charge distribution during the first methyl transfer.

<p>(R: Reactant, TS: S _N2 transition state, P: product).</p