A5076090370- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Alzheimer's disease research and treatments
- Cannabis and Cannabinoid Research
- Enzyme function and inhibition
- Chemical Synthesis and Analysis
- Enzyme Structure and Function
- Chemical synthesis and alkaloids
- Synthesis and biological activity
- Pharmacological Receptor Mechanisms and Effects
- Neuropeptides and Animal Physiology
- Neurotransmitter Receptor Influence on Behavior
- Cancer, Hypoxia, and Metabolism
- Chemical Reactions and Isotopes
- Biochemical and Molecular Research
- Sphingolipid Metabolism and Signaling
- Microtubule and mitosis dynamics
- Enzyme Catalysis and Immobilization
- Phosphodiesterase function and regulation
- Neuroscience and Neuropharmacology Research
- Chemical Reaction Mechanisms
- Nicotinic Acetylcholine Receptors Study
University of Urbino
2021-2025
University of Birmingham
2018-2024
Italian Institute of Technology
2009-2021
Heptares Therapeutics (United Kingdom)
2017-2018
University of Bologna
2004-2015
Istituto Nazionale di Fisica Nucleare, Sezione di Genova
2015
Torrey Pines Institute For Molecular Studies
2008-2009
Scripps Research Institute
2008-2009
Molsoft (United States)
2008-2009
Molecular dynamics (MD) and related methods are close to becoming routine computational tools for drug discovery. Their main advantage is in explicitly treating structural flexibility entropic effects. This allows a more accurate estimate of the thermodynamics kinetics associated with drug-target recognition binding, as better algorithms hardware architectures increase their use. Here, we review theoretical background MD enhanced sampling methods, focusing on free-energy perturbation,...
The use of multiple X-ray protein structures has been reported to be an efficient alternative for the representation binding pocket flexibility needed accurate small molecules docking. However, docking performance individual single conformations varies widely, and adding certain ensemble is even counterproductive. Here we used a very large diverse benchmark 1068 99 therapeutically relevant proteins, first, compare single-conformation and, second, find properties best-performing conformers...
Many available methods aimed at incorporating the receptor flexibility in ligand docking are computationally expensive, require a high level of user intervention, and were tested only on benchmarks limited size diversity. Here we describe four-dimensional (4D) approach that allows seamless incorporation conformational ensembles single simulation reduces sampling time while preserving accuracy traditional ensemble docking. The was benchmark 99 therapeutically relevant proteins 300 diverse...
Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The were designed taking advantage the crystal structures acetylcholinesterase (AChE) in complex with derivatives. Sixteen derivatives synthesized, using spacers different lengths chemical composition. molecules then tested as inhibitors AChE binders N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some new nanomolar showed micromolar affinities for NMDAR. All also selectivity...
Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, development of multitarget drugs which involved both pathways might represent a promising therapeutic strategy. Accordingly, reported here is discovery 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as first class molecules able simultaneously modulate BACE-1 GSK-3β. Notably, one triazinone showed...
The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such Alzheimer's disease (AD). concurrent inhibition of the validated AD targets β-secretase (BACE-1) glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid tau protein cascades been identified promising therapeutic strategy. In our study, curcumin was lead compound for simultaneous targets; therefore, synthetic efforts were dedicated obtaining small library...
Abstract The study of biomolecular interactions between a drug and its biological target is paramount importance for the design novel bioactive compounds. In this paper, we report on use molecular dynamics (MD) simulations machine learning to binding mechanism transition state analogue (DADMe–immucillin-H) purine nucleoside phosphorylase (PNP) enzyme. Microsecond-long MD allow us observe several events, following different dynamical routes reaching diverse configurations. These are used...
REV-ERBα and REV-ERBβ nuclear receptors regulate several physiological processes, including circadian rhythm metabolism. A previous study reported the gene to be co-overexpressed with ERBB2 in breast cancer cell lines. Surprisingly, we found that tumor types, a number of lines, predominantly express variant. This pattern was independent ER status, opposite non-cancer mammary epithelial HMEC cells, which major Consistent this molecular profile, REV-ERB target genes both metabolic pathways...
Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which CPU-demanding not yet particularly accurate. We recently reported new scaled-MD-based protocol, showed potential prediction...
The representation of protein flexibility is still a challenge for the state-of-the-art flexible ligand docking protocols. In this article, we use large and diverse benchmark to prove that possible improve consistently cross-docking performance against single receptor conformation, using an equilibrium ensemble binding site conformers. contained 28 proteins, our method predicted top-ranked near native poses 20% more efficiently than receptor. multiple conformations were derived from...
The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and prioritize for experimental testing a comparatively small diverse set compounds with expected activity against target. Several studies have pointed out that the performance can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic conformations, powerful way discretely representing protein plasticity, exploited protocols...
One of the main obstacles toward discovery effective anti-Alzheimer drugs is multifactorial nature its etiopathology. Therefore, use multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, well cognitive neurogenic functions, are fostered come. In this respect, we report herein on first class BACE-1/GSK-3β dual inhibitors based a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton,...
The binding of sulfonamides to human carbonic anhydrase II (hCAII) is a complex and long-debated example protein-ligand recognition interaction. In this study, we investigate the para-substituted n-alkyl hydroxyethylene-benzenesulfonamides, providing complete reconstruction their pathway hCAII by means large-scale molecular dynamics simulations, density functional calculations, surface plasmon resonance (SPR) measurements, X-ray crystallography experiments. Our analysis shows that...
In this paper, we introduce the BiKi Life Sciences suite. This software makes it easy for computational medicinal chemists to run ad hoc molecular dynamics protocols in a novel and task-oriented environment; as notebook, (acronym of Binding Kinetics) keeps memory any activity together with dependencies among them. It offers unique accelerated protein–ligand binding/unbinding methods other useful tools gain actionable knowledge from simulations simplify drug discovery process.
Exchange of mitochondrial subunits C15ORF48 and NDUFA4 occurs during macrophage activation in vitro inflammatory disease.