Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning

Abstract

Target-based design and repositioning are mainstream strategies of drug discovery. Numerous drug design and repositioning projects have been launched to fight the ongoing COVID-19 pandemic. The resulting drug candidates have often failed due to the misprediction of their target-bound structures. The determination of water positions of such structures is particularly challenging due to the large number of possible drugs and the diversity of their hydration patterns. To answer this challenge and help correct predictions, we introduce a new protocol HydroDock, which can build hydrated drug–target complexes from scratch. HydroDock requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, we built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head. As HydroDock supplied otherwise undetermined structural details, it can be recommended to improve the reliability of future design and repositioning of antiviral drug candidates and many other ligands with an influence of water structure on their mechanism of action.

Inside and Out of the Pore: Comparing Interactions and Molecular Dynamics of Influenza A M2 Viroporin Complexes in Standard Lipid Bilayers

“…MD simulations describing the interactions of chloride ions with M2TM WT apo-protein ,, or M2TM complexes with Amt or Rim , showed that more than one chloride anion can enter simultaneously the M2 pore at acidic pH in the C open conformation . At acidic pH, two H37 (in alternating α-helices) to all four H37 residues are protonated resulting in Q2–Q4 states and the chloride ions counteract the positive electrostatic potential in the center of the pore.…”

“…Despite the increased frequency of MD simulations performed for influenza A M2, there is no study for the description of consistent setup conditions and simulation parameters or methodology, from docking calculations to MD that can provide results comparable with the experimental measurements for this reference viroporin. During a revised submission of the present work, a new molecular docking algorithm was reported 63 that was able to predict adamantane blockers inside the M2 pore without considering structural waters as part of the protein in docking calculations.…”

Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design

“…The final binding modes of known inhibitors were determined by X-ray crystallography [22,24], and the fast computational docking method (Methods Section) was verified to reproduce these experimental binding conformations correctly (Figure S1 and Table S1). However, it has been shown that a simple series of fast docking calculations cannot deliver a fully systematic mapping [14,35] of all possible binding modes. Therefore, the present NetBinder strategy (Figure 2) applies a systematic search technique called Wrap 'n' Shake [35], and PMs were detected by wrapping the entire inner surface of the binding cavity of apo myosin 2 (Figure 1) in numerous copies of BS.…”

“…Recently, molecular dynamics (MD) has emerged as a suitable approach for identifying PMs of specific drugs binding to specific targets [6,[8][9][10][11][12]. MD can generate appropriate samples of target-ligand complex structures, allowing conformational flexibility and explicit solvent effects [13,14]. Here, we present an MD-based approach to the study of myosin 2 (a motor protein with a crucial role in eukaryotic motility) and one of its well-known inhibitors.…”

“…Sci. 2022, 23, x FOR PEER REVIEW 2 of 17 and explicit solvent effects [13,14]. Here, we present an MD-based approach to the study of myosin 2 (a motor protein with a crucial role in eukaryotic motility) and one of its wellknown inhibitors.…”