PLATO (Polypharmacology pLATform predictiOn) is an easy-to-use drug discovery web platform, which has been designed with a two-fold objective: to fish putative protein drug targets and to compute ...bioactivity values of small molecules. Predictions are based on the similarity principle, through a reverse ligand-based screening, based on a collection of 632,119 compounds known to be experimentally active on 6004 protein targets. An efficient backend implementation allows to speed-up the process that returns results for query in less than 20 s. The graphical user interface is intuitive to give practitioners easy input and transparent output, which is available as a standard report in portable document format. PLATO has been validated on thousands of external data, with performances better than those of other parallel approaches. PLATO is available free of charge (http://plato.uniba.it/ accessed on 13 April 2022).
In the last decade, selective modulators of type-2 cannabinoid receptor (CB
) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our ...body, CB
actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB
modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB
agonists in the last five years. Against this background, here we discuss the most recent evidence of the protective effects of CB
against pathological conditions, emphasizing central nervous system disorders, bone and synovial diseases, and cancer. We also summarize the most recent advances in the development of CB
agonists, focusing on the correlation between different chemical classes and diverse therapeutic applications. Data mining includes a review of the CB
ligands disclosed in patents also released in the last five years. Finally, we discuss how the recent elucidation of CB
tertiary structure has provided new details for the rational design of novel and more selective CB
agonists, thus supporting innovative strategies to develop effective therapeutics. Our overview of the current knowledge on CB
agonists provides pivotal information on the structure and function of different classes of molecules and opens possible avenues for future research.
Chemical space modelling has great importance in unveiling and visualising latent information, which is critical in predictive toxicology related to drug discovery process. While the use of ...traditional molecular descriptors and fingerprints may suffer from the so-called curse of dimensionality, complex networks are devoid of the typical drawbacks of coordinate-based representations. Herein, we use chemical space networks (CSNs) to analyse the case of the developmental toxicity (Dev Tox), which remains a challenging endpoint for the difficulty of gathering enough reliable data despite very important for the protection of the maternal and child health. Our study proved that the Dev Tox CSN has a complex non-random organisation and can thus provide a wealth of meaningful information also for predictive purposes. At a phase transition, chemical similarities highlight well-established toxicophores, such as aryl derivatives, mostly neurotoxic hydantoins, barbiturates and amino alcohols, steroids, and volatile organic compounds ether-like chemicals, which are strongly suspected of the Dev Tox onset and can thus be employed as effective alerts for prioritising chemicals before testing.
The fusion oncoprotein Bcr-Abl is an aberrant tyrosine kinase responsible for chronic myeloid leukemia and acute lymphoblastic leukemia. The auto-inhibition regulatory module observed in the ...progenitor kinase c-Abl is lost in the aberrant Bcr-Abl, because of the lack of the
-myristoylated cap able to bind the myristoyl binding pocket also conserved in the Bcr-Abl kinase domain. A way to overcome the occurrence of resistance phenomena frequently observed for Bcr-Abl orthosteric drugs is the rational design of allosteric ligands approaching the so-called myristoyl binding pocket. The discovery of these allosteric inhibitors although very difficult and extremely challenging, represents a valuable option to minimize drug resistance, mostly due to the occurrence of mutations more frequently affecting orthosteric pockets, and to enhance target selectivity with lower off-target effects. In this perspective, we will elucidate at a molecular level the structural bases behind the Bcr-Abl allosteric control and will show how artificial intelligence can be effective to drive the automated de novo design towards off-patent regions of the chemical space.
Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs ...synthesized, except
and
, had potent and/or significant selective inhibitory effects on MAO-B.
potently inhibited MAO-B with an IC
value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively.
, and
were also active against MAO-B, both had an IC
value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE.
most potently inhibited MAO-A (IC
= 0.88 µM) and also significantly inhibited MAO-B (IC
= 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor.
and
inhibited AChE with IC
values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of
for MAO-B was higher than that of
(SI = 778.6 vs. 222.2), but the IC
value (0.028 µM) was slightly lower than that of
(0.018 µM). In reversibility experiments, inhibitions of MAO-B by
and
were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with K
values of 0.0075 and 0.010 µM, respectively. Our results show that
and
are potent, selective MAO-B inhibitors, and
is a candidate of dual-targeting molecule for MAO-B and AChE.
Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and ...AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we ...explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure–activity relationship (SAR) studies aimed at investigating para- or meta-benzamidine as the P1 basic group as well as diversely decorated aryl moieties as P4 fragments. To this end, twenty-three malonamide derivatives were synthesized and tested as inhibitors of fXa and thrombin (thr); the molecular determinants behind potency and selectivity were also studied by employing molecular docking. The malonamide linker, compared to the glycinamide one, does significantly increase anti-fXa potency and selectivity. The meta-benzamidine (P1) derivatives bearing 2′,4′-difluoro-biphenyl as the P4 moiety proved to be highly potent reversible fXa-selective inhibitors, achieving inhibition constants (Ki) in the low nanomolar range. The most active compounds were also tested against cholinesterase (ChE) isoforms (acetyl- or butyrylcholinesterase, AChE, and BChE), and some of them returned single-digit micromolar inhibition potency against AChE and/or BChE, both being drug targets for symptomatic treatment of mild-to-moderate Alzheimer’s disease. Compounds 19h and 22b were selected as selective fXa inhibitors with potential as multimodal neuroprotective agents.
People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and ...non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium-hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.
Sixteen compounds (TR1–TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B ...inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 μM, followed by TR2 (IC50 = 0.27 μM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood–brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.
Nine compounds (MO1-MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds ...potently inhibited MAO-B; MO1 most potently inhibited with an IC
50
value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC
50
= 6.1 µM), followed by MO9 (IC
50
= 12.01 µM) and MO7 most potently inhibited MAO-A (IC
50
= 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (K
i
= 0.018 µM); MO5 reversibly competitively inhibited AChE (K
i
= 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (K
i
= 7.04 µM). MO1, MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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