title: A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins.
abstract: The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of nanoseconds of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite ( http://www.bikitech.com [accessed July 21, 2015]). Then, instead of applying arbitrary selection criteria, that is, RMSD, pharmacophore properties, or enrichment performances, we allowed the linear discriminant analysis algorithm implemented in FLAP ( http://www.moldiscovery.com [accessed July 21, 2015]) to automatically choose the best performing conformational states among medoids and X-ray structures. Retrospective virtual screenings confirmed that ensemble receptor protocols outperform single rigid receptor approaches, proved that computationally generated conformations comprise the same quantity/quality of information included in X-ray structures, and pointed to the MD-FLAP approach as a valuable tool for improving VS performances.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi 103, 41125 Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , Via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Benedetti
authors.affiliation: CONCEPT Lab, Italian Institute of Technology , via Morego 30, 16163 Genova, Italy.|BiKi Technologies s.r.l. , via XX Settembre 33, 16121 Genova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Decherchi
authors.affiliation: CONCEPT Lab, Italian Institute of Technology , via Morego 30, 16163 Genova, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Rocchia
authors.affiliation: CompuNet, Italian Institute of Technology , via Morego 30, 16163 Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Health Science, University Magna Graecia of Catanzaro , Campus "S Venuta", Viale Europa 88100, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of Health Science, University Magna Graecia of Catanzaro , Campus "S Venuta", Viale Europa 88100, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Molecular Discovery Limited , 215 Marsh Road, Pinner Middlesex, London HA5-5NE, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Baroni
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , Via Elce di Sotto 8, 06123 Perugia, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D001665:Binding Sites; D019992:Databases as Topic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins