Giovanni Bottegoni

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The representation of protein flexibility is still a challenge for the state-of-the-art flexible ligand docking protocols. In this article, we use a large and diverse benchmark to prove that is possible to improve consistently the cross-docking performance against a single receptor conformation, using an equilibrium ensemble of binding site conformers. The(More)
The use of multiple X-ray protein structures has been reported to be an efficient alternative for the representation of the binding pocket flexibility needed for accurate small molecules docking. However, the docking performance of the individual single conformations varies widely, and adding certain conformations to an ensemble is even counterproductive.(More)
The endocannabinoid anandamide is removed from the synaptic space by a selective transport system, expressed in neurons and astrocytes, that remains molecularly uncharacterized. Here we describe a partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH-like anandamide transporter (FLAT),(More)
Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a(More)
Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael(More)
The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account(More)
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 of limited size and diversity. Here we describe the four-dimensional (4D) docking approach that allows seamless incorporation of receptor conformational(More)
Eight monomeric congeners, related to the multitarget lead candidate memoquin, were prepared and evaluated at multiple targets to determine their profile against Alzheimer's disease. 2-4 bind to AChE with similar low nanomolar affinities and function as effective inhibitors of amyloid aggregation. The most potent monovalent ligand 2 also inhibits BACE-1 in(More)
Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking(More)
Combined docking and molecular dynamics (MD) simulations were carried out in order to investigate the binding mode of propidium at the human acetylcholinesterase (HuAChE) peripheral site. Two different docking protocols followed by cluster analyses were performed, allowing the identification of five high-populated and low-energy configuration families. To(More)