Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics

Abstract

Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.

Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma

“…One of the computational techniques able to capture these events is supervised molecular dynamics (SuMD) [ 40 ]. Indeed, this can be efficiently used to analyze the recognition pathway of small molecule ligands with a protein of interest, as already demonstrated in different scenarios on very distinct targets [ 41 , 42 , 43 , 44 ].…”

Structural Manipulations of Marine Natural Products Inspire a New Library of 3-Amino-1,2,4-Triazine PDK Inhibitors Endowed with Antitumor Activity in Pancreatic Ductal Adenocarcinoma

“…One of the techniques which have shown success in this field is Supervised Molecular Dynamics (SuMD) [ 46 ], an unbiased enhanced sampling approach able to proficiently describe the recognition event between a ligand and a biological target in the nanosecond timescale. This method has been already applied to several targets and scenarios, giving very promising results [ 47 , 48 , 49 , 50 ]…”

Fighting Antimicrobial Resistance: Insights on How the Staphylococcus aureus NorA Efflux Pump Recognizes 2-Phenylquinoline Inhibitors by Supervised Molecular Dynamics (SuMD) and Molecular Docking Simulations

“…The 2:7 ratio obtained for productive over nonproductive replica was in line with our expectation based on the observation achieved for other transmembrane proteins. Of note, we previously noted that the main aspect affecting this ratio is not the affinity between the small molecule and the binding site ,, but the complexity of the recognition event at the molecular level ( e.g., target and ligand flexibility, peculiar molecular mechanism) …”

“…Of note, we previously noted that the main aspect affecting this ratio is not the affinity between the small molecule and the binding site 38,44,61 but the complexity of the recognition event at the molecular level (e.g., target and ligand flexibility, peculiar molecular mechanism). 62 3.2.1. NorA-PQQ16P Recognition Pathway.…”