Your browser doesn't support javascript.
Virtual Double-System Single-Box: A Nonequilibrium Alchemical Technique for Absolute Binding Free Energy Calculations: Application to Ligands of the SARS-CoV-2 Main Protease.
Macchiagodena, Marina; Pagliai, Marco; Karrenbrock, Maurice; Guarnieri, Guido; Iannone, Francesco; Procacci, Piero.
  • Macchiagodena M; Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
  • Pagliai M; Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
  • Karrenbrock M; Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
  • Guarnieri G; ENEA, Portici Research Centre, DTE-ICT-HPC P.le E. Fermi, 1, I-80055 Portici (NA), Italy.
  • Iannone F; ENEA, Portici Research Centre, DTE-ICT-HPC P.le E. Fermi, 1, I-80055 Portici (NA), Italy.
  • Procacci P; Dipartimento di Chimica "Ugo Schiff", Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
J Chem Theory Comput ; 16(11): 7160-7172, 2020 Nov 10.
Article in English | MEDLINE | ID: covidwho-889116
Semantic information from SemMedBD (by NLM)
1. proline DISRUPTS Low activity
Subject
proline
Predicate
DISRUPTS
Object
Low activity
2. Antiviral Agents TREATS COVID-19
Subject
Antiviral Agents
Predicate
TREATS
Object
COVID-19
3. proline DISRUPTS Low activity
Subject
proline
Predicate
DISRUPTS
Object
Low activity
4. Antiviral Agents TREATS COVID-19
Subject
Antiviral Agents
Predicate
TREATS
Object
COVID-19
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)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Endopeptidases / Viral Nonstructural Proteins / Betacoronavirus Limits: Humans Language: English Journal: J Chem Theory Comput Year: 2020 Document Type: Article Affiliation country: Acs.jctc.0c00634

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Cysteine Endopeptidases / Viral Nonstructural Proteins / Betacoronavirus Limits: Humans Language: English Journal: J Chem Theory Comput Year: 2020 Document Type: Article Affiliation country: Acs.jctc.0c00634