Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

Abstract

Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure–activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes.

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

“…Docking tests were performed using the software Glide [ 12 ] and Autodock Vina [ 60 ]. Glide offers a complete solution for ligand–receptor docking and is widely used for drug discovery [ 83 , 84 ], virtual screening [ 85 , 86 ], structure-activity relationship analysis [ 87 , 88 , 89 ], pharmacophore modeling [ 90 , 91 , 92 ], evaluation of enzymatic reaction pathways [ 93 , 94 ], and other studies. All grid boxes for molecular docking were centered in the ligand position coming from the crystal structures.…”

Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies

“…Standard (SP) and extra-precision (XP) modes were run in Glide [35], but only the XP mode was used to find adequate poses for all ligands [36]. The Glide protocol and parameters were the same as reported in previous reports [37][38][39]. The selection of poses was based on looking for the observed protein-ligand interactions patterns in the reported PDB crystals of LasB, and in the selection of the lowest scoring energy from among the adequate poses.…”

Computational aided mechanistic understanding of Camellia sinensis bioactive compounds against co‐chaperone p23 as potential anticancer agent

“…The free energy calculations for the p23 protein docked with potential ligand was calculated in Prime molecular mechanics generalized born surface area (MMGBSA) module (Schrödinger Release 2019‐2:Prime, Schrödinger, LLC, New York, NY, 2019) using MMGBSA protocol as reported earlier . This approach was implicated on 500 snapshots extracted from the 20 ns simulation trajectories where explicit TIP4P water molecules and ions were removed from the respective complex as reported earlier . Following, free binding energy was then calculated using Equation .…”

“…41,42 This approach was implicated on 500 snapshots extracted from the 20 ns simulation trajectories where explicit TIP4P water molecules and ions were removed from the respective complex as reported earlier. 43 Following, free binding energy was then calculated using Equation (1).…”