In silico design of peptide inhibitors of tubulin: amyloid-β as a lead compound

Microtubule is one of the most studied targets in cancer research. Stabilizing and destabilizing of the microtubule by targeting its building block tubulin are common mechanisms of microtubule targeting agents. Cancer associates inversely with Alzheimer's disease (AD). So the rate of developing AD is significantly slower in patients with cancer and vice versa. Amyloid-beta (A beta) peptide inhibits tubulin polymerization and induces apoptotic death of cancer cells. We studied the interactions of A beta with tubulin using protein-protein docking and MD simulation. A beta bond to the vicinity of the vinblastine binding site and interacted with the H6-H7 loop. Interaction of A beta with H6-H7 loop blocked nucleotide exchange and may be attributed as a possible reason for blocking of tubulin polymerization. We designed new A beta-based peptidic inhibitors of tubulin using visual inspection and alanine scanning method. P1 (FRHYHHFFELV) and P9 (HYHHF) bound efficiently to tubulin and also interacted with the H6-H7 loop. Obtained results indicated that proposed peptides could potentially inhibit nucleotide exchange as A beta. Communicated by Ramaswamy H. Sarma