Structure-based drug design e sintesi di nuovi bioisosteri eterociclici della funzione beta-diketoacida come inibitori dell'enzima HIV-1 integrasi

In questo lavoro, seguendo l’approccio della bioisosteria non classica, la porzione β-diketonica I è stata incorporata nei nuclei ossazolico III e pirazolico IV e sono stati disegnati gli acidi indolil-3-ossazolici 4ac e indolil-3-pirazolici 5a-c. Inoltre la funzione β-diketoacida II, sostituita con un nucleo 3-idrossi-pirrolo-2,5-dionico V, contemplato in letteratura come bioisostero di tale struttura, ha portato ai derivati 6a-c. Le molecole progettate sono state sottoposte ad uno studio di docking al fine di di valutare preliminarmente l’attività inibitoria tramite la costante di inibizione Ki in accordo con il razionale Structure-based drug design

Searching for novel carbonic anhydrase inhibitors: from virtual screening to the lab bench

Carbonic Anhydrases (CAs) are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate both in prokaryotes and eukaryotes. In this context, Computer Aided Drug Design strategies have emerged as powerful tools in the modern drug discovery paradigm. In particular, using ligand- and pharmacophore-based virtual screening approaches, we identified novel chemical entities with original chemotypes, that showed an interesting and selective inhibitory activity in nanomolar/low micromolar range toward CA I and CAII, isoforms. Herein, we present the hit-to-lead optimization process for these prototypes

Synthesis and study of polyhydroxylated phenol derivatives with potential cosmetic and phytoiatric applications

Tyrosinase (polyphenol oxidase, E.C. 1.14.18.1) and laccase (phenol oxidase, E.C. 1.10.3.2) are multifunctional copper-containing enzymes, that are keys in melanin biosynthesis, melanisation in animals and browning in plants. Our study is aimed to prepare new monomer and dimer phenol derivatives as potential inhibitors of melanin production starting from natural hydroxylated aromatic units

Natural phenolic inhibitors of trichothecene biosynthesis by the wheat fungal pathogen <i>Fusarium culmorum</i>: a computational insight into the structure-activity relationship

A model of the trichodiene synthase (TRI5) of the wheat fungal pathogen and type-B trichothecene producer Fusarium culmorum was developed based on homology modelling with the crystallized protein of F. sporotrichioides. Eight phenolic molecules, namely ferulic acid 1, apocynin 2, propyl gallate 3, eugenol 4, Me-dehydrozingerone 5, eugenol dimer 6, magnolol 7, and ellagic acid 8, were selected for their ability to inhibit trichothecene production and/or fungal vegetative growth in F. culmorum. The chemical structures of phenols were constructed and partially optimised based on Molecular Mechanics (MM) studies and energy minimisation by Density Functional Theory (DFT). Docking analysis of the phenolic molecules was run on the 3D model of F. culmorum TRI5. Experimental biological activity, molecular descriptors and interacting-structures obtained from computational analysis were compared. Besides the catalytic domain, three privileged sites in the interaction with the inhibitory molecules were identified on the protein surface. The TRI5-ligand interactions highlighted in this study represent a powerful tool to the identification of new Fusarium-targeted molecules with potential as trichothecene inhibitors

Design, synthesis, molecular modeling and anti-HIV 1 integrase activity of a series of photoactivable diketo acid-containing inhibitors as affinity probes

Photoaffinity Labelling (PL) is a powerful method in the chemical proteomic approach of protein functions. This method is especially useful for the identification of ligand-binding sites of target proteins and for the investigation of ligand–receptor interactions. The use of affinity-labeled inhibitors to covalently modify the site of interaction and subsequent analysis of the protein have been very effective in providing useful informations about inhibitor binding for a multitude of therapeutic target proteins. Therefore, it could reasonably be applied in drug discovery and development processes. For example, such approach can be used to obtain structural information detailing the association between the enzyme HIV-1 integrase (IN) and inhibitors under development

Design and synthesis of bis-amide and hydrazide-containing derivatives of malonic acid as potential HIV-1 integrase inhibitors

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site

Factors Impacting σ- and π-Hole Regions as Revealed by the Electrostatic Potential and Its Source Function Reconstruction: The Case of 4,4'-Bipyridine Derivatives

Positive electrostatic potential (V) values are often associated with σ- and π-holes, regions of lower electron density which can interact with electron-rich sites to form noncovalent interactions. Factors impacting σ- and π-holes may thus be monitored in terms of the shape and values of the resulting V. Further precious insights into such factors are obtained through a rigorous decomposition of the V values in atomic or atomic group contributions, a task here achieved by extending the Bader–Gatti source function (SF) for the electron density to V. In this article, this general methodology is applied to a series of 4,4'-bipyridine derivatives containing atoms from Groups VI (S, Se) and VII (Cl, Br), and the pentafluorophenyl group acting as a π-hole. As these molecules are characterized by a certain degree of conformational freedom due to the possibility of rotation around the two C–Ch bonds, from two to four conformational motifs could be identified for each structure through conformational search. On this basis, the impact of chemical and conformational features on σ- and π-hole regions could be systematically evaluated by computing the V values on electron density isosurfaces (VS) and by comparing and dissecting in atomic/atomic group contributions the VS maxima (VS,max) values calculated for different molecular patterns. The results of this study confirm that both chemical and conformational features may seriously impact σ- and π-hole regions and provide a clear analysis and a rationale of why and how this influence is realized. Hence, the proposed methodology might offer precious clues for designing changes in the σ- and π-hole regions, aimed at affecting their potential involvement in noncovalent interactions in a desired way

Comparative enantioseparation of planar chiral ferrocenes on polysaccharide-based chiral stationary phases.

Planar chiral ferrocenes are well-known compounds that have attracted interest for application in synthesis, catalysis, material science, and medicinal chemistry for several decades. In spite of the fact that asymmetric synthesis procedures for obtaining enantiomerically enriched ferrocenes are available, sometimes, the accessible enantiomeric excess of the chiral products is unsatisfactory. In such cases and for resolution of racemic planar chiral ferrocenes, enantioselective high-performance liquid chromatography (HPLC) on polysaccharide-based chiral stationary phases (CSPs) has been used in quite a few literature articles. However, although moderate/high enantioselectivities have been obtained for planar chiral ferrocenes bearing polar substituents, the enantioseparation of derivatives containing halogens, or exclusively alkyl groups, remains rather challenging. In this study, the enantioseparation of ten planar chiral 1,2- and 1,3-disubstituted ferrocenes was explored by using five polysaccharide-based CSPs under multimodal elution conditions. Baseline enantioseparations were achieved for nine analytes with separation factors (α) ranging from 1.20 to 2.92. The presence of π-extended systems in the analyte structure was shown to impact affinity of the most retained enantiomer toward amylose-based selectors, observing retention times higher than 80 min with methanol-containing mobile phases (MPs). Electrostatic potential (V) analysis and molecular dynamics (MD) simulations were used in order to study interaction modes at the molecular level

Attività biologica e studi di docking di derivati bis-ammidici dell'acido 5,6- diidrossiindolo-2-carbossilico come inibitori dell'enzima HIV-1 integrasi

In un precedente studio, nel tentativo di identificare nuovi inibitori dell'HIV-1 integrasi, è stata da noi considerata la modifica strutturale dell'estere feniletilico dell'acido caffeico I (CAPE), il primo prodotto naturale inibitore dell'IN identificato, incorporando il legame vinilico del CAPE all'interno di una struttura rigida costituita dall'anello pirrolico. In questa comunicazione, a completamento dello studio svolto, noi presentiamo i dati relativi all'attività  inibitoria enzimatica per i derivati IIIe-i, lo studio SAR per tutti i derivati ed uno studio di docking nel sito attivo dell'HIV-1 IN eseguito al fine di investigare le possibili interazioni tra i ligandi e gli a.a. del sito catalitico