Dynamic Docking of Conformationally Constrained Macrocycles: Methods and Applications

Abstract

Many natural products consist of large and flexible macrocycles that engage their targets via multiple contact points. This combination of contained flexibility and large contact area often allows natural products to bind at target surfaces rather than deep pockets, making them attractive scaffolds for inhibiting protein-protein interactions and other challenging therapeutic targets. The increasing ability to manipulate such compounds either biosynthetically or via semisynthetic modification means that these compounds can now be considered as starting points for medchem campaigns rather than solely as ends. Modern medchem benefits substantially from rational improvements made on the basis of molecular docking. As such, docking methods have been enhanced in recent years to deal with the complicated binding modalities and flexible scaffolds of macrocyclic natural products and natural product-like structures. Here, we comprehensively review methods for treating and docking these large macrocyclic scaffolds and discuss some of the resulting advances in medicinal chemistry.

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

“…Cyclic peptides exhibit a lever of selectivity to protein surfaces and can be developed to be modulators of PPIs. To design active cyclic peptides as potential therapeutics, many computational methods have been developed to generate cyclic peptide libraries through virtual screening . In 2014, Bobay et al performed a computational screening of 160,000 potential cyclic peptides to search potential calbindin‐D28K inhibitors.…”

Exhaustive Exploration of the Conformational Landscape of Small Cyclic Peptides Using a Robotics Approach

“…1 This is partially due to advances in chemistry to produce stable cyclic peptides as well as to the development of biotechnologies avoiding most of the drawbacks objected to peptides such as enzyme digestion or membrane penetration. [2][3][4][5][6] Peptides combine the advantages of proteins and small molecules: they have high selectivity as proteins, and metabolic stability, oral availability and low immunogenicity, as small molecules. 2,[6][7][8] Compared to small ligands, peptides can occupy larger surfaces of interaction and reach higher specificities.…”

An Efficient ABC_DE_Based Hybrid Algorithm for Protein–Ligand Docking

“…Its application shortens the process of drug research and reduces the cost of drug discovery. Protein–ligand docking, as an important part of CADD, is a computer simulation to predict the binding pose when the three-dimensional structures of protein receptors and ligands are known [3,4,5,6]. The purpose of protein–ligand docking is to find the conformation with the lowest energy when a ligand binds the active region of a receptor.…”