1D alignment of proteins and other nanoparticles by using reversible covalent bonds on cyclic peptide nanotubes

Self-assembling cyclic peptide nanotubes are supramolecular structures whose diameter and external surface properties are precisely controlled. In this communication we describe a general strategy to align different molecules on top...

Insight into the Binding Energetics of Targeted Reversible Covalent Inhibitors of the SARS-CoV-2 Main Protease

The main protease (Mpro) of the SARS-CoV-2 virus is an attractive therapeutic target for developing antivirals to combat COVID-19. Mpro is essential for the replication cycle of the SARS-CoV-2 virus, so inhibiting Mpro blocks a vital piece of the cell replication machinery of the virus. A promising strategy to disrupt the viral replication cycle is to design inhibitors that bind to the active site cysteine (Cys145) of the Mpro. Cysteine targeted covalent inhibitors are gaining traction in drug discovery owing to the benefits of improved potency and extended drug-target engagement. An interesting aspect of these inhibitors is that they can be chemically tuned to form a covalent, but reversible bond, with their targets of interest. Several small-molecule cysteine-targeting covalent inhibitors of the Mpro have been discovered—some of which are currently undergoing evaluation in early phase human clinical trials. Understanding the binding energetics of these inhibitors could provide new insights to facilitate the design of potential drug candidates against COVID-19. Motivated by this, we employed rigorous absolute binding free energy calculations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to estimate the energetics of binding of some promising reversible covalent inhibitors of the Mpro. We find that the inclusion of enhanced sampling techniques such as replica-exchange algorithm in binding free energy calculations can improve the convergence of predicted non-covalent binding free energy estimates of inhibitors binding to the Mpro target. In addition, our results indicate that binding free energy calculations coupled with multiscale simulations can be a useful approach to employ in ranking covalent inhibitors to their targets. This approach may be valuable in prioritizing and refining covalent inhibitor compounds for lead discovery efforts against COVID-19 and future coronavirus infections.

Insight into the Binding Energetics of Targeted Reversible Covalent Inhibitors of the SARS-CoV-2 Main Protease

The main protease (Mpro) of the SARS-CoV-2 virus is an attractive therapeutic target for developing antivirals to combat COVID-19. Mpro is essential for the replication cycle of the SARS-CoV-2 virus, so inhibiting Mpro blocks a vital piece of the cell replication machinery of the virus. A promising strategy to disrupt the viral replication cycle is to design inhibitors that bind to the active site cysteine (Cys145) of the Mpro. Cysteine targeted covalent inhibitors are gaining traction in drug discovery owing to the benefits of improved potency and extended drug-target engagement. An interesting aspect of these inhibitors is that they can be chemically tuned to form a covalent, but reversible bond, with their targets of interest. Several small-molecule cysteine-targeting covalent inhibitors of the Mpro have been discovered—some of which are currently undergoing evaluation in early phase human clinical trials. Understanding the binding energetics of these inhibitors could provide new insights to facilitate the design of potential drug candidates against COVID-19. Motivated by this, we employed rigorous absolute binding free energy calculations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations to estimate the energetics of binding of some promising reversible covalent inhibitors of the Mpro. We find that the inclusion of enhanced sampling techniques such as replica-exchange algorithm in binding free energy calculations can improve the convergence of predicted non-covalent binding free energy estimates of inhibitors binding to the Mpro target. In addition, our results indicate that binding free energy calculations coupled with multiscale simulations can be a useful approach to employ in ranking covalent inhibitors to their targets. This approach may be valuable in prioritizing and refining covalent inhibitor compounds for lead discovery efforts against COVID-19 and future coronavirus infections.

Nano-structured dynamic Schiff base cues as robust self-healing polymers for biomedical and tissue engineering applications: a review

Polymer materials are vulnerable to damages, failures, and degradations, making them economically unreliable. Self-healing polymers, on the other hand, are multifunctional materials with superior properties of autonomic recovery from physical damages. These materials are suitable for biomedical and tissue engineering in terms of cost and durability. Schiff base linkages-based polymer materials are one of the robust techniques owing to their simple self-healing mechanism. These are dynamic reversible covalent bonds, easy to fabricate at mild conditions, and can self-reintegrate after network disruption at physiological conditions making them distinguished. Here we review self-healing polymer materials based on Schiff base bonds. We discuss the Schiff base bond formation between polymeric networks, which explains the self-healing phenomenon. These bonds have induced 100% recovery in optimal cases.