Well-tempered metadynamics calculations of free energy surfaces of benzothiadiazine derivatives in aqueous solution

Abstract

ABSTRACTKRAS oncogenes are the largest family of mutated RAS isoforms, participating in about 30% of all cancers. Due to their paramount medical importance, enormous effort is being devoted to the development of inhibitors using clinical tests, wet-lab experiments and drug design, being this a preliminary step in the process of creating new drugs, prior to synthesis and clinical testing. One central aspect in the development of new drugs is the characterization of all species that can be used for treatment. In this aim we propose a computational framework based on combined all-atom molecular dynamics and metadynamics simulations in order to accurately access the most stable conformational variants for several derivatives of a recently proposed small-molecule, called DBD15-21-22. Free energy calculations are essential to unveil mechanisms at the atomic scale like binding affinities or dynamics of stable states. Considering specific atom-atom distances and torsional angles as reliable reaction coordinates we have obtained free-energy landscapes by well-tempered metadynamics simulations, revealing local and global minima of the free-energy hypersurface. We have observed that a variety of stable states together with transitions states are clearly detected depending on the particular species, leading to predictions on the behaviour of such compounds in ionic aqueous solution.