title: The ligand binding mechanism to purine nucleoside phosphorylase elucidated via molecular dynamics and machine learning.
abstract: The study of biomolecular interactions between a drug and its biological target is of paramount importance for the design of novel bioactive compounds. In this paper, we report on the use of molecular dynamics (MD) simulations and machine learning to study the binding mechanism of a transition state analogue (DADMe-immucillin-H) to the purine nucleoside phosphorylase (PNP) enzyme. Microsecond-long MD simulations allow us to observe several binding events, following different dynamical routes and reaching diverse binding configurations. These simulations are used to estimate kinetic and thermodynamic quantities, such as kon and binding free energy, obtaining a good agreement with available experimental data. In addition, we advance a hypothesis for the slow-onset inhibition mechanism of DADMe-immucillin-H against PNP. Combining extensive MD simulations with machine learning algorithms could therefore be a fruitful approach for capturing key aspects of drug-target recognition and binding.
authors.affiliation: 1] CONCEPT Lab, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy [2] BiKi Technologies s.r.l., via XX Settembre 33, 16121 Genova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Decherchi
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Berteotti
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: CONCEPT Lab, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Rocchia
authors.affiliation: 1] CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy [2] Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000465:Algorithms; D016000:Cluster Analysis; D006801:Humans; D007700:Kinetics; D008024:Ligands; D000069550:Machine Learning; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055503:Protein Multimerization; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry* / Q000378:metabolism*; D011744:Pyrimidinones / Q000737:chemistry / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors
chemical_list: C508755:DADMe-immucillin H; D008024:Ligands; D011744:Pyrimidinones; D011759:Pyrrolidines; D011683:Purine-Nucleoside Phosphorylase