Abstract

The molecular mechanics energies combined with the Poisson–Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor–ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. Antimicrobial peptides (AMPs) which predominantly act via membrane active mechanisms have emerged as an exciting class of antimicrobial agents with tremendous potential to overcome the global epidemic of antibiotics-resistant infections. The first generation of AMPs derived from natural sources as diverse as plants, insects and humans has provided a wealth of compositional and structural information to design novel synthetic AMPs with enhanced antimicrobial potencies and selectivities, reduced cost of production due to shorter sequences and improved stabilities under physiological conditions. As a rational result we discovered for the first time the GENEA-Antimamphiler-109 utilizing Rational Elaborated Common Strategies employed MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities for the efficient in silico optimization of an accesible synthetically (AMPs) peptidomimetic-similar to an amphiphile-based pharmacophoric agent as a promising enhanced therapeutic antimicrobial agent.

Keywords

MM/PBSA;MM/GBSA; methods; ligand-binding affinities; Rational Elaborated; Common Strategies; in silico; optimization; accesible; synthetically; (AMPs) peptidomimetic; amphiphile-based; pharmacophoric agent; therapeutic antimicrobial agent;