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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316057

ABSTRACT

We have applied a computational strategy, based on the synergy of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CL-pro of the SARS-Cov2 Coronavirus. Based on the recently resolved 6LU7 PDB structure, ligands were generated using a multimodal structure-based design and then optimally docked to the 6LU7 monomer. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases, irrespectively of the protonation state of the catalytic CYS-HIS dyad. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement. Molecular dynamics calculations fully confirm the stability in the 3CL-pro binding pocket of the most potent binder identified by docking, namely a chlorophenyl-pyridyl-carboxamide derivative.

2.
J Comput Aided Mol Des ; 35(6): 721-729, 2021 06.
Article in English | MEDLINE | ID: covidwho-1549468

ABSTRACT

We systematically tested the Autodock4 docking program for absolute binding free energy predictions using the host-guest systems from the recent SAMPL6, SAMPL7 and SAMPL8 challenges. We found that Autodock4 behaves surprisingly well, outperforming in many instances expensive molecular dynamics or quantum chemistry techniques, with an extremely favorable benefit-cost ratio. Some interesting features of Autodock4 predictions are revealed, yielding valuable hints on the overall reliability of docking screening campaigns in drug discovery projects.


Subject(s)
Proteins/chemistry , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Reproducibility of Results , Retrospective Studies , Software , Solvents/chemistry , Thermodynamics
3.
J Mol Graph Model ; 110: 108042, 2022 01.
Article in English | MEDLINE | ID: covidwho-1517349

ABSTRACT

We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , Coronavirus 3C Proteases , Humans , Lactams , Leucine , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles , Proline , Protease Inhibitors
4.
J Chem Inf Model ; 61(11): 5320-5326, 2021 11 22.
Article in English | MEDLINE | ID: covidwho-1493001

ABSTRACT

We describe a step-by-step protocol for the computation of absolute dissociation free energy with GROMACS code and PLUMED library, which exploits a combination of advanced sampling techniques and nonequilibrium alchemical methodologies. The computational protocol has been automated through an open source Python middleware (HPC_Drug) which allows one to set up the GROMACS/PLUMED input files for execution on high performing computing facilities. The proposed protocol, by exploiting its inherent parallelism and the power of the GROMACS code on graphical processing units, has the potential to afford accurate and precise estimates of the dissociation constants in drug-receptor systems described at the atomistic level. The procedure has been applied to the calculation of the absolute dissociation free energy of PF-07321332, an oral antiviral proposed by Pfizer, with the main protease (3CLpro) of SARS-CoV-2.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Antiviral Agents , Entropy , Lactams , Leucine , Nitriles , Proline , SARS-CoV-2
5.
Chem Phys Lett ; 750: 137489, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1025637

ABSTRACT

We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CLpro of the SARS-CoV2 Coronavirus. Based on the X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement.

6.
J Chem Theory Comput ; 16(11): 7160-7172, 2020 Nov 10.
Article in English | MEDLINE | ID: covidwho-889116

ABSTRACT

In the context of drug-receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CLpro) of SARS-CoV-2. The core structures of 3CLpro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The nature of binding in the 3CLpro active site and the involved residues besides the CYS-HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CLpro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.


Subject(s)
Betacoronavirus/enzymology , Cysteine Endopeptidases/metabolism , Viral Nonstructural Proteins/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Humans , Ligands , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Protein Binding , SARS-CoV-2 , User-Computer Interface , Viral Nonstructural Proteins/antagonists & inhibitors
7.
Chem Commun (Camb) ; 56(62): 8854-8856, 2020 Aug 04.
Article in English | MEDLINE | ID: covidwho-635466

ABSTRACT

Using a combination of enhanced sampling molecular dynamics techniques and non-equilibrium alchemical transformations with full atomistic details, we have shown that hydroxychloroquine (HCQ) may act as a mild inhibitor of important functional proteins for SARS-CoV2 replication, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.


Subject(s)
Cysteine Endopeptidases/metabolism , Hydroxychloroquine/metabolism , Molecular Dynamics Simulation , Papain/metabolism , RNA-Dependent RNA Polymerase/metabolism , Viral Nonstructural Proteins/metabolism , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Papain-Like Proteases , Cysteine Endopeptidases/chemistry , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/therapeutic use , Pandemics , Papain/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry
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