In silico design of tubulin-targeted antimitotic peptides

Abstract

Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.

Alanine-shaving Mutagenesis to Determine Key Interfacial Residues Governing the Assembly of a Nano-cage Maxi-ferritin

“…S13-S15). Although the side chain of Asp-56 is aligned with Arg-30 and that of Glu-60 is aligned with Lys-33, all four are proximal in space and may form an extended hydrogen-bonding "hot stretch" (38) as opposed to a more canonical hot spot. Therefore, conceptually isolating these into simple binary interactions is not possible.…”

Targeted Polypeptide–Microtubule Aggregation with Cucurbit[8]uril for Enhanced Cell Apoptosis

“…[7,8] Thed esign of our system was based on the inspection of aselected polypeptide containing ten amino acids,which was identified by computational analysis and exhibited antimitotic activity by competitive binding with the a-tubulin subunit. [9] To further explore the curative effect of supramolecular intertubular aggregation, we present an entirely self-assembled microtubular system, which is fabricated by the combination of primary tubulin-tubulin heterodimerization, specific peptide-tubulin recognition, and cooperative host-guest complexation. In our case,t he chemical modification of ab enzylimidazolium moiety with an antimitotic polypeptide (BP) did not interfere with its original tubulin-targeting ability,b ut it provided af unctional anchoring point to noncovalently interact with cucurbiturils (CB [7] and CB [8]).…”

9‐Fluorenone‐2‐Carboxylic Acid as a Scaffold for Tubulin Interacting Compounds

“…The crude product was purified by column chromatography on silica gel (CH 2 Cl 2 /n-hexane = 5:1) to give 11 as a yellow powder in 58 % yield. 1 7-Ethyl-9-oxo-9H-fluorene-2-carboxylic acid (12): NaOH (9.2 mg, 0.231 mmol) was added to a stirred solution of 11 (15.4 mg, 0.0578 mmol) in CH 2 Cl 2 /MeOH (9:1; 1 mL). The reaction mixture was stirred at RT for 28 h, then concentrated under vacuum, acidified with 1 m HCl, and extracted with CHCl 3 (3 15 mL).…”

“…MTs are thus the target of many anticancer drugs that exert their cytotoxic action during the cell-division process. [11] In a previous study, [12] we have modeled the network of longitudinal interactions between the a and the b subunit of different tubulin heterodimers allowing MTs formation and stability.…”