Docking of Covalent Ligands: Challenges and Approaches

Abstract

Covalent ligands have recently regained considerable attention in drug discovery. The rational design of such ligands, however, is still faced with particular challenges, mostly related to the fact that covalent bond formation is a quantum mechanical phenomenon which cannot adequately be handled by the force fields or empirical approaches typically used for noncovalent protein-ligand interactions. Although the necessity for quantum chemical approaches is clear, they cannot yet routinely be applied on large data sets of ligands or for a broader exploration of binding modes in docking calculations. On the other hand, technical solutions for performing docking calculations with covalent ligands are available, but their scope is normally quite limited. Scoring functions typically neglect the contribution from covalent bond formation completely. In this situation, the question arises how to approach covalent ligands and which methods to choose for their docking and design.

Docking-based virtual screening studies aiming at the covalent inhibition of SARS-CoV-2 MPro by targeting the cysteine 145

“…( Gentile et al, 2020 ; Ngo et al, 2020 ) A strategy of achieving irreversible inhibition of this protease has also been addressed by the design of compounds to create a covalent bond with the cysteine 145 residue (Cys145) of the catalytic dyad. (Pillaiyar, et al, 2020) While classical docking studies are widely reported in the literature,( Kitchen et al, 2004 ) docking studies for covalent protein inhibition are less common,( Kumalo et al, 2015 ; Sotriffer, 2018 ) in particular with SARS-CoV-2 main protease. ( Liu et al, 2020 ; Paul et al, 2020 ) Despite covalent inhibition approaches are less studied because the requirement of a nucleophilic residue is a structural limitation and they can be considered as harmful, the resurgence of covalent drugs encourage to also consider covalent inhibition.…”

Which Stereoinductor Is Better for Asymmetric Functionalization of α‐Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations

“…The 3D structure of a molecule is determined not only by its basic structural network, which is defined by covalent bonding, but also by noncovalent interactions. Intricate noncovalent interactions govern many areas of biology and chemistry, including the design of new materials and drugs . Weak noncovalent interactions encompass hydrogen bonding, dipole–dipole interactions, steric repulsion, and London dispersion forces.…”

In Silico Screening of Phytochemicals of Ocimum Sanctum Against Main Protease of SARS-CoV-2

“…They all have potential to form C-S (Cys145) covalent bond leading to irreversible covalent inhibitors. Covalent inhibitors have been approved as drugs by FDA since a decadereversing the trend of disallowing it with a fear of toxic effects (Awoonor-Williams et al, 2017;Sotriffer, 2018;Ghosh et al, 2019). Several advantages of the covalent drugs have encouraged its designing in the present time.…”