Molecular Dynamics Simulation Reveal the Mechanism of Resistance of Mutant Actins to Latrunculin A – Insight into Specific Modifications to Design Novel Drugs to Overcome Resistance

Background: Mutant actins D157E and R183A-D184A are reported to resist the anticancer drug Latrunculin A (LAT); though identified, the mechanism of resistance is not clearly understood. Objective: To design better molecules that can overcome the resistance caused by mutations it is important to define precise pharmacophoric regions in LAT based on the mechanism of resistance on the mutant actin –LAT interactions. Methods: To address this we have conducted 20 nano seconds (ns) simulation of mutant actins – LAT complex and compared it with the 20ns simulation of wild actin – LAT complex. Functions as the binding free energy, distance between LAT and binding site residues, LAT and actin domains, dihedral angle analysis, motional correlation were studied of these simulations. Results: Grounded on these studies, four sites in LAT are identified to be crucial for modification. Bulkier ring moieties containing nitrogen in place of the double bonded oxygen in the macrocyclic lactone ring may be considered to establish interactions with Glu214. The nitrogen in 2-thiazolidinone moiety can be substituted with a hydrophobic ring to stabilise the interaction with the Asp157Glu and the oxygen in the cyclohexane of LAT with hydrophilic groups to strengthen their interaction with Tyr69. The nitrogen of the 2-thiazolidinone moiety can be replaced with nitrogen containing rings to improve inhibition of the actin polymerisation. Apart from this chemical groups on the sulphur of 2-thiazolidinone moiety to improve the hydrophobic interaction with actin is also identified for modification. Conclusion: Based on this a combinatorial library of 46 LAT analogs was generated and docked with the wild and mutant actins to identify potent leads to become anti-actin anticancer drugs.