Computer-aided design of amino acid-based therapeutics: a review

Farhadi, Tayebeh; Hashemian, Seyed MohammadReza

Recently, PepCrawler 101 and FlexPepDock 102 were developed as the peptide docking tools. 18 It is reported that FlexPepDock 102 has sub-angstrom accuracy in reproducing the crystal structures of protein-peptide complexes. 103 All of the FlexPepDock-based methods assume previous information about the peptide-binding site. 13 AnchorDock, a recently described algorithm, allows powerful blind docking calculations through relaxing the constraint. 104 The program predicts anchoring origins on a protein surface. Following recognition of the anchoring origins, an assumed peptide conformation is refined using an anchor-constrained molecular dynamic process. 105 HADDOCK, a well-known protein-protein docking tool, has been recently expanded to run the flexible peptide-protein docking. 105 To handle a docking procedure, HADDOCK uses ambiguous interaction restraints based on the experimental information about intermolecular interactions. This rigid body peptide docking is followed through a flexiblesimulated annealing process. The novel HADDOCK strategy initiates docking computations from an ensemble of three dissimilar peptide conformations (eg, α-helix, extended and polyproline-II) that are high informative inputs. 105 CABS-dock is a recently introduced protein-peptide docking tool and runs a primary docking procedure whose outcomes can be refined by other tools such as FlexPepDock. 106 In the primary phase of the procedure, random conformations of a peptide are predicted and located around the protein target of interest. The process is followed by replica exchange Monte Carlo dynamics. Subsequently, 10 models are selected for the last optimization using the Modeller tool to gain accurate scoring and ranking poses. 13, 106 GalaxyPepDock was developed to use experimentally resolved protein-peptide structures for running the template-based docking pooled by flexible energy-based optimization. 107 Atomistic simulation Atomistic Monte Carlo and molecular dynamics simulations are accurate, but they are meticulous techniques to investigate peptide-protein binding interactions. These techniques can also detect the thermodynamic profile and trajectory included in protein-peptide identification. These methods predict the association among conformations of a peptide in solution or protein. 108 In a study, in order to describe the binding of a decapeptide to the cognate SH3 receptor, a long-term molecular dynamic simulation was used and a two-state model was built. 109 In the first step, a relatively quick diffusion phase, nonspecific encounter complexes were generated and stabilized by using electrostatic energy. The secondary step was a slow modification phase, in which the water molecules were emptied out from the space between the peptide ligand and the receptor. 109 In another report, by using Monte Carlo method, the mentioned two-state model was verified to trace some oligopeptide routes for binding to various PDZ (Post synaptic density protein, Drosophila disc large tumor suppressor, and Zonula occludens-1 protein) domains. 110 Drug Design, Development and Therapy 2018:12 submit your manuscript | www.dovepress.com