A5042202366- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Cholinesterase and Neurodegenerative Diseases
- HIV/AIDS drug development and treatment
- Aldose Reductase and Taurine
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- HIV Research and Treatment
- Enzyme function and inhibition
- Protein purification and stability
- Microbial Natural Products and Biosynthesis
- Multiple Myeloma Research and Treatments
- Biochemical and Molecular Research
- Receptor Mechanisms and Signaling
- Nicotinic Acetylcholine Receptors Study
- Peptidase Inhibition and Analysis
- Research on Leishmaniasis Studies
- Tuberculosis Research and Epidemiology
- Trypanosoma species research and implications
- Photochromic and Fluorescence Chemistry
- Advanced Polymer Synthesis and Characterization
University of Würzburg
2016-2025
University of Milan
2022
Instituto de Histología y Embriología de Mendoza
2022
Consejo Nacional de Investigaciones Científicas y Técnicas
2022
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
2022
University of Padua
2022
Icesi University
2022
Philipps University of Marburg
2002-2010
Virginia Commonwealth University
2008
University of Parma
2008
Docking of the 5CITEP inhibitor to snapshots a 2 ns HIV-1 integrase MD trajectory indicated previously uncharacterized trench adjacent active site that intermittently opens. Further docking studies novel ligands with potential bind both regions showed greater selective affinity when able trench. Our ranking is open experimental testing, and our approach suggests new target for therapeutics.
ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTTarget Flexibility: An Emerging Consideration in Drug Discovery and Design†Pietro Cozzini*‡§, Glen E. Kellogg*#, Francesca Spyrakis‡§, Donald J. Abraham‡, Gabriele Costantino∥, Andrew Emerson⊥, Fanelli∞, Holger Gohlke×, Leslie A. Kuhn¶, Garrett M. Morris●, Modesto Orozco◇, Thelma Pertinhez◆, Menico Rizzi∇, Christoph Sotriffer⊗View Author Information Department of General Inorganic Chemistry, University Parma, Via G.P. Usberti 17/A 43100, Italy,...
Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors used the treatment Alzheimer's disease. To design new cholinesterase inhibitors, different structure-based strategies was followed, including modification compounds from a previously developed library fragment-based approach. This led to selection heterodimeric structures as potential inhibitors. Synthesis evaluation selected candidates confirmed that designed were...
A major shortcoming of empirical scoring functions for protein-ligand complexes is the low degree correlation between predicted and experimental binding affinities, as frequently observed not only large diverse data sets but also SAR series individual targets. Improvements can be envisaged by developing new descriptors, employing larger training higher quality, resorting to more sophisticated regression methods. Herein, we describe use SFCscore descriptors develop an improved function means...
Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target are potent acetyl- (AChE) and butyrylcholinesterase (BChE) in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both catalytic active site (CAS) peripheral anionic (PAS) of AChE. Yet upon irradiation light, mechanism interaction varied photochromic form to another,...
Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) its regulatory scaffolding proteins. One these the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs transcription factors including MYC. The wide influence dysfunctional HMT complexes typically upregulated MYC levels in diverse tumor types suggested WDR5 an attractive drug target. Indeed,...
Empirical scoring functions to calculate binding affinities of protein-ligand complexes have been calibrated based on experimental structure and affinity data collected from public industrial sources. Public were taken the AffinDB database, whereas access was gained through Scoring Function Consortium (SFC), a collaborative effort with various pharmaceutical companies Cambridge Crystallographic Data Center. More than 850 obtained by collection procedure subsequently used setup different...
Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds 2-thiophenyl compound 2p as most potent inhibitor eqBChE (KC = 14.3 nM) and also hBChE 19.7 nM). The transfer carbamate moiety onto active site under release phenolic that themselves act neuroprotectants. By...
In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding enzyme. A set compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 10 methylene groups between heterocycle) in residue synthesized characterized vitro for their affinity, kinetics, hydrolysis. These novel BChE are highly selective hBChE over human...
Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits Alzheimer's disease, since both pharmacological actions are able enhance cholinergic neurotransmission the cortex. However, whereas inhibitors prevent hydrolysis acetylcholine also peripherally, antagonists will raise levels mostly brain due predominant occurrence central nervous system. In this work, we designed synthesized two...
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed for neurodegenerative diseases incorporate antioxidant effects without losing affinity selectivity at HDAC6. Structure-activity relationships led compound 10b as a hybrid molecule showing pronounced selective inhibition HDAC6 (IC50 = 30.7 nM, > 25-fold over other subtypes). This shows comparable DPPH radical scavenging ability acid, ORAC...
To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable inhibitors. The compounds were able specifically influence different kinetic parameters inhibition process light. For one compound, a 10-fold difference in IC50-values (44.6 nM cis, 424 trans) vitro was translated an "all or nothing" response with complete...
Polymer self-assembly leading to cooling-induced hydrogel formation is relatively rare for synthetic polymers and typically relies on H-bonding between repeat units. Here, we describe a non-H-bonding mechanism reversible order-order (sphere-to-worm) transition related thermogelation of solutions polymer self-assemblies. A multitude complementary analytical tools allowed us reveal that significant fraction the hydrophobic hydrophilic units underlying block copolymer in close proximity gel...
A new application of DrugScore is reported in which the knowledge-based pair potentials serve as objective function docking optimizations. The Lamarckian genetic algorithm AutoDock used to search for favorable ligand binding modes guided by grids representations protein site. approach found be successful many cases where DrugScore-based re-ranking already docked conformations does not yield satisfactory results. Compared scoring function, yields slightly superior results flexible docking.
Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in open vivo system. However, lack accurate kinetic structural data for a series congeneric compounds hinders rational design inhibitors with decreased off-rates. Therefore, we chose Staphylococcus aureus enoyl-ACP reductase (saFabI)--an target development new anti-staphylococcal drugs--as...