Publications by authors named "Orazio Nicolotti"

108 Publications

CATMoS: Collaborative Acute Toxicity Modeling Suite.

Environ Health Perspect 2021 Apr 30;129(4):47013. Epub 2021 Apr 30.

Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Background: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. models built using existing data facilitate rapid acute toxicity predictions without using animals.

Objectives: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 ( value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [ ()], and nontoxic chemicals ().

Methods: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches.

Results: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with results.

Discussion: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.
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http://dx.doi.org/10.1289/EHP8495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086800PMC
April 2021

Piperazine-substituted chalcones: a new class of MAO-B, AChE, and BACE-1 inhibitors for the treatment of neurological disorders.

Environ Sci Pollut Res Int 2021 Mar 20. Epub 2021 Mar 20.

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC values of 0.65 and 0.71 μM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 μM, although PC4 inhibited AChE by 56.6% (IC = 8.77 μM). Compound PC3 effectively inhibited BACE-1 (IC = 6.72 μM), and PC10 and PC11 moderately inhibited BACE-1 (IC =14.9 and 15.3 μM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with K values of 0.63 ± 0.13 and 0.53 ± 0.068 μM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.
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http://dx.doi.org/10.1007/s11356-021-13320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980107PMC
March 2021

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential.

Molecules 2021 Jan 12;26(2). Epub 2021 Jan 12.

Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent -phenylene DHPPIQ Schiff base exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC) = 12 μM), the bis-DHPPIQ showed a good inhibitory activity on self-induced β-amyloid (Aβ) aggregation (IC = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base .
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http://dx.doi.org/10.3390/molecules26020359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827648PMC
January 2021

Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations.

J Enzyme Inhib Med Chem 2021 Dec;36(1):188-197

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea.

Nine compounds () 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; most potently inhibited with an IC value of 0.030 µM, followed by (0.25 µM). most potently inhibited AChE (IC = 6.1 µM), followed by (IC = 12.01 µM) and most potently inhibited MAO-A (IC = 7.1 µM). was a reversible mixed-type inhibitor of MAO-B ( = 0.018 µM); reversibly competitively inhibited AChE ( = 2.52 µM); and reversibly noncompetitively inhibited AChE ( = 7.04 µM). , and crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that is a selective inhibitor of MAO-B and that is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1080/14756366.2020.1842390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808749PMC
December 2021

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents.

ACS Chem Neurosci 2021 01 4;12(2):340-353. Epub 2021 Jan 4.

Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of -bridged cyclopenta[]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound and its close congeners and acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.
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http://dx.doi.org/10.1021/acschemneuro.0c00706DOI Listing
January 2021

Design, synthesis and biological evaluation of imidazole and triazole-based carbamates as novel aromatase inhibitors.

Eur J Med Chem 2021 Feb 25;211:113115. Epub 2020 Dec 25.

Unit of Medicinal Chemistry, Department of Pharmacy, "G. D'Annunzio" University, Chieti, Italy.

In the search for novel aromatase inhibitors, a series of triazole and imidazole-based carbamate derivatives were designed and synthesized. Final compounds were thus evaluated against human aromatase by in vitro kinetic experiments in a fluorimetric assay in comparison with letrozole. The effect of most active derivatives 13a and 15c was then evaluated in vitro on the human breast cancer cell line MCF7 by MTT assay, cytotoxicity assay (LDH release) and cell cycle analysis, revealing a dose-dependent inhibition profile of cell viability and low micromolar IC values. In addition, docking simulations were also carried out to elucidate at a molecular level of detail the binding modes adopted to target human aromatase.
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http://dx.doi.org/10.1016/j.ejmech.2020.113115DOI Listing
February 2021

Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer's Disease.

Molecules 2020 Dec 7;25(23). Epub 2020 Dec 7.

Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer's disease. The newly synthesized molecules spanned their IC values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the 'active' compounds from the 'inactive' (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of 'active' compounds, i.e., those achieving finite IC values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set ( = 45, q = 0.596) and in the external test set ( = 14, r = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein.
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http://dx.doi.org/10.3390/molecules25235773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731220PMC
December 2020

Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors.

Molecules 2020 Nov 17;25(22). Epub 2020 Nov 17.

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea.

Twelve pyridazinones (-) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. was found to be the most potent MAO-B inhibitor with an IC value of 0.013 µM, followed by (IC = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by bromo substitution () than by bromo substitution (). For substitution, inhibitory potencies for MAO-B were as follows: -Cl () > -N(CH) () > -OCH () > Br () > F () > -CH () > -H (). and efficiently inhibited MAO-A with IC values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). and were found to be reversible and competitive inhibitors of MAO-B with K values of 0.014 and 0.0071, respectively. Moreover, was less toxic to healthy fibroblast cells (L929) than . Molecular docking simulations with MAO binding sites returned higher docking scores for and with MAO-B than with MAO-A. These results suggest that and are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.
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http://dx.doi.org/10.3390/molecules25225371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698448PMC
November 2020

(Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors.

ACS Comb Sci 2020 11 13;22(11):592-599. Epub 2020 Oct 13.

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad-678557, Kerala, India.

Fourteen (hetero-)(arylidene)arylhydrazide derivatives (-) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound most potently inhibited MAO-B with an IC value of 0.025 ± 0.0019 μM; and exhibited high IC values as well. Most of the compounds weakly inhibited MAO-A, except (IC = 3.31 ± 0.41 μM). Among the active compounds, showed the highest selectivity index (SI) of 174 for MAO-B, followed by (SI = 132). and effectively inhibited AChE with IC values of 15.7 ± 6.52 and 16.5 ± 7.29 μM, respectively, whereas the other compounds were weak inhibitors of AChE. was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with values of 0.96 ± 0.19 and 0.024 ± 0.0077 μM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.
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http://dx.doi.org/10.1021/acscombsci.0c00136DOI Listing
November 2020

Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to.

Molecules 2020 Sep 14;25(18). Epub 2020 Sep 14.

Dipartimento di Farmacia Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", 70125 Bari, Italy.

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.
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http://dx.doi.org/10.3390/molecules25184210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570842PMC
September 2020

Selected 1,3-Benzodioxine-Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors.

ChemMedChem 2020 Dec 14;15(23):2257-2263. Epub 2020 Oct 14.

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.

Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.
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http://dx.doi.org/10.1002/cmdc.202000491DOI Listing
December 2020

Drug Design of Targeted Chemical Libraries Based on Artificial Intelligence and Pair-Based Multiobjective Optimization.

J Chem Inf Model 2020 10 9;60(10):4582-4593. Epub 2020 Sep 9.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona, 4, I-70126 Bari, Italy.

Artificial intelligence and multiobjective optimization represent promising solutions to bridge chemical and biological landscapes by addressing the automated design of compounds as a result of a humanlike creative process. In the present study, we conceived a novel pair-based multiobjective approach implemented in an adapted SMILES generative algorithm based on recurrent neural networks for the automated design of new molecules whose overall features are optimized by finding the best trade-offs among relevant physicochemical properties (MW, logP, HBA, HBD) and additional similarity-based constraints biasing specific biological targets. In this respect, we carried out the design of chemical libraries targeting neuraminidase, acetylcholinesterase, and the main protease of severe acute respiratory syndrome coronavirus 2. Several quality metrics were employed to assess drug-likeness, chemical feasibility, diversity content, and validity. Molecular docking was finally carried out to better evaluate the scoring and posing of the generated molecules with respect to X-ray cognate ligands of the corresponding molecular counterparts. Our results indicate that artificial intelligence and multiobjective optimization allow us to capture the latent links joining chemical and biological aspects, thus providing easy-to-use options for customizable design strategies, which are especially effective for both lead generation and lead optimization. The algorithm is freely downloadable at https://github.com/alberdom88/moo-denovo and all of the data are available as Supporting Information.
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http://dx.doi.org/10.1021/acs.jcim.0c00517DOI Listing
October 2020

Design, synthesis and biological evaluation of 3,5-diaryl isoxazole derivatives as potential anticancer agents.

Bioorg Med Chem Lett 2020 10 23;30(19):127427. Epub 2020 Jul 23.

Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey. Electronic address:

The present study was carried out in the attempt to synthesize a new class of potential anticancer agents comprising eleven compounds (24-34) sharing the 3,5-diarylisoxazole as a core. The chemical structure of the new synthesized compounds was established by IR, H NMR, C NMR and elemental analysis. Their biological potential towards prostate cancer was evaluated by using cancer PC3 cells and non-tumorigenic PNT1a cells. Interestingly, compound 26 distinguished from others with a quite high selectivity value that is comparable to 5-FU. The binding mode of 26 towards Ribosomal protein S6 kinase beta-1 (S6K1) was investigated at a molecular level of detail by employing docking simulations based on GLIDE standard precision as well as MM-GBSA calculations.
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http://dx.doi.org/10.1016/j.bmcl.2020.127427DOI Listing
October 2020

Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.

Int J Mol Sci 2020 Jun 23;21(12). Epub 2020 Jun 23.

Dipartimento di Farmacia Scienze del Farmaco Università degli Studi di Bari "Aldo Moro", via Orabona 4, Bari 70125, Italy.

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.
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http://dx.doi.org/10.3390/ijms21124469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352889PMC
June 2020

A New Potent and Selective Monoamine Oxidase-B Inhibitor with Extended Conjugation in a Chalcone Framework: 1-[4-(Morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one.

ChemMedChem 2020 09 15;15(17):1629-1633. Epub 2020 Jul 15.

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, 678557, Kerala, India.

The general blueprint for the design of monoamine oxidase-B (MAO-B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one (MO10) was prepared by the condensation of 4'-morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC value of 0.044 μM along with a selectivity index of 366.13. The IC value was better than that of lazabemide (IC value of 0.063 μM), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO-B, with a K value of 0.0080 μM. The observation of recovery of MAO-B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC value of 195.44 μg/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood-brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO-B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.
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http://dx.doi.org/10.1002/cmdc.202000305DOI Listing
September 2020

Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors.

Molecules 2020 May 18;25(10). Epub 2020 May 18.

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea.

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.
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http://dx.doi.org/10.3390/molecules25102356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288026PMC
May 2020

Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor.

ACS Med Chem Lett 2020 May 7;11(5):869-876. Epub 2020 Feb 7.

Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy.

Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (±)--, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of by HPLC and (ii) preparing two close achiral analogues of , i.e., compounds and . An eudismic ratio as high as 20 was observed for the (-) enantiomer of -. The X-ray crystal structure of the complex between the (-)-- eutomer (coded as ) and AChE was determined at 2.8 Å, and docking calculation results suggested that the eutomer in (1,3) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1,3) configuration. The achiral analogues and were less effective in inhibiting AChE compared to (±)--, but interestingly butylamide emerged as a potent inhibitor of butyrylcholinesterase (BChE).
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http://dx.doi.org/10.1021/acsmedchemlett.9b00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236231PMC
May 2020

A Comprehensive Review of Monoamine Oxidase-A Inhibitors in their Syntheses and Potencies.

Comb Chem High Throughput Screen 2020 ;23(9):898-914

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea.

Background: Monoamine oxidases (MAOs) play a crucial role during the development of various neurodegenerative disorders. There are two MAO isozymes, MAO-A and MAO-B. MAO-A is a flavoenzyme, which binds to the outer mitochondrial membrane and catalyzes the oxidative transformations of neurotransmitters like serotonin, norepinephrine, and dopamine.

Materials And Methods: Focus on synthetic studies has culminated in the preparation of many MAOA inhibitors, and advancements in combinatorial and parallel synthesis have accelerated the developments of synthetic schemes. Here, we provided an overview of the synthetic protocols employed to prepare different classes of MAO-A inhibitors. We classified these inhibitors according to their molecular scaffolds and the synthetic methods used.

Results: Various synthetic and natural derivatives from a different class of MAO-A inhibitors were reported.

Conclusion: The review provides a valuable tool for the development of a new class of various selective MAO-A inhibitors for the treatment of depression and other anxiety disorders.
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http://dx.doi.org/10.2174/1386207323666200428091306DOI Listing
January 2020

Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor.

Molecules 2020 Apr 15;25(8). Epub 2020 Apr 15.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.

A simple, quick, easy and cheap tandem mass spectrometry (MS/MS) method for the determination of adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP) has been newly developed. This novel MS/MS method was applied for the evaluation of the inhibitory effect of a novel 2-oxo-1,2-dihydropyridine-3-carbonitrile derivative, also named DF492, on PDE3 enzyme activity in comparison to its parent drug milrinone. Molecule DF492, with an IC of 409.5 nM, showed an inhibition of PDE3 greater than milrinone (IC = 703.1 nM). To explain the inhibitory potential of DF492, molecular docking studies toward the human PDE3A were carried out with the aim of predicting the binding mode of DF492. The presence of different bulkier decorating fragments in DF492 was pursued to shift affinity of this novel molecule toward PDE3A compared to milrinone in accordance with both the theoretical and experimental results. The described mass spectrometric approach could have a wider potential use in kinetic and biomedical studies and could be applied for the determination of other phosphodiesterase inhibitor molecules.
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http://dx.doi.org/10.3390/molecules25081817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221589PMC
April 2020

Design of enamides as new selective monoamine oxidase-B inhibitors.

J Pharm Pharmacol 2020 Jul 3;72(7):916-926. Epub 2020 Apr 3.

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India.

Objectives: To develop of new class of selective and reversible MAO-B inhibitors from enamides.

Methods: Syntheses of the titled derivatives (AD1-AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines.

Key Findings: Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC values of 0.11 and 0.10 µm, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µm, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC values of 4.21 and 5.95 µm, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with K values of 0.044 ± 0.0036 and 0.039 ± 0.0047 µm, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B.

Conclusions: These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.
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http://dx.doi.org/10.1111/jphp.13264DOI Listing
July 2020

CoMPARA: Collaborative Modeling Project for Androgen Receptor Activity.

Environ Health Perspect 2020 02 7;128(2):27002. Epub 2020 Feb 7.

Istituto di Ricerche Farmacologiche "Mario Negri", IRCCS, Milan, Italy.

Background: Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) approaches and computational modeling.

Objectives: In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP).

Methods: The CoMPARA list of screened chemicals built on CERAPP's list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast™ metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast™/Tox21 HTS assays.

Results: The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set.

Discussion: The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program's Integrated Chemical Environment. https://doi.org/10.1289/EHP5580.
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http://dx.doi.org/10.1289/EHP5580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064318PMC
February 2020

Design and synthesis of fluorescent ligands for the detection of cannabinoid type 2 receptor (CB2R).

Eur J Med Chem 2020 Feb 7;188:112037. Epub 2020 Jan 7.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, via Orabona 4, 70125, Bari, Italy. Electronic address:

The Cannabinoid 2 receptor, CB2R, belonging to the endocannabinoid system, ECS, is involved in the first steps of neurodegeneration and cancer evolution and progression and thus its modulation may be exploited in the therapeutic and diagnostic fields. However, CB2Rs distribution and signaling pathways in physiological and pathological conditions are still controversial mainly because of the lack of reliable diagnostic tools. With the aim to produce green and safe systems to detect CB2R, we designed a series of fluorescent ligands with three different green fluorescent moieties (4-dimethylaminophthalimide, 4-DMAP, 7-nitro-4-yl-aminobenzoxadiazole, NBD, and Fluorescein-thiourea, FTU) linked to the N1-position of the CB2R pharmacophore N-adamantyl-4-oxo-1,4-dihydroquinoline-3-carboxamide through polymethylene chains. Compound 28 emerged for its compromise between good pharmacodynamic properties (CB2R K = 130 nM and no affinity vs the other subtype CB1R) and optimal fluorescent spectroscopic properties. Therefore, compound 28 was studied through FACS (saturation and competitive binding studies) and fluorescence microscopy (visualization and competitive binding) in engineered cells (CB2R-HEK293 cells) and in diverse tumour cells. The fluoligand binding assays were successfully set up, and affinity values for the two reference compounds GW405833 and WIN55,212-2, comparable to the values obtained by radioligand binding assays, were obtained. Fluoligand 28 also allowed the detection of the presence and quantification of the CB2R in the same cell lines. The interactions of compound 28 within the CB2R binding site were also investigated by molecular docking simulations, and indications for the improvement of the CB2R affinity of this class of compounds were provided. Overall, the results obtained through these studies propose compound 28 as a safe and green alternative to the commonly used radioligands for in vitro investigations.
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http://dx.doi.org/10.1016/j.ejmech.2020.112037DOI Listing
February 2020

Structure-Based Identification and Design of Angiotensin Converting Enzyme-Inhibitory Peptides from Whey Proteins.

J Agric Food Chem 2020 Jan 2;68(2):541-548. Epub 2020 Jan 2.

Institute of Sciences of Food Production (CNR-ISPA) National Council of Research , Via G. Amendola, 122/O , 70126 Bari , Italy.

Besides their nutritional value, whey protein (WP) peptides are food components retaining important pharmacological properties for controlling hypertension. We herein report how the use of complementary experimental and theoretical investigations allowed the identification of novel angiotensin converting enzyme inhibitory (ACEI) peptides obtained from a WP hydrolysate and addressed the rational design of even shorter sequences based on molecular pruning. Thus, after bromelain digestion followed by a 5 kDa cutoff ultrafiltration, WP hydrolysate with ACEI activity was fractioned by RP-HPLC; 2 out of 23 collected fractions retained ACEI activity and were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the face of 128 identified peptides, molecular docking was carried out to prioritize peptides and to rationally guide the design of novel shorter and bioactive sequences. Therefore, 11 peptides, consisting of 3-6 amino acids and with molecular weights in the range from 399 to 674 Da, were rationally designed and then purchased to determine the IC value. This approach allowed the identification of two novel peptides: MHI and IAEK with IC ACEI values equal to 11.59 and 25.08 μM, respectively. Interestingly, we also confirmed the well-known ACEI IPAVF with an IC equal to 9.09 μM. In light of these results, this integrated approach could pave the way for high-throughput screening and identification of new peptides in dairy products. In addition, the herein proposed ACEI peptides could be exploited for novel applications both for food production and pharmaceuticals.
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http://dx.doi.org/10.1021/acs.jafc.9b06237DOI Listing
January 2020

Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics.

J Biomol Struct Dyn 2020 Oct 20;38(17):5219-5229. Epub 2019 Dec 20.

Consiglio Nazionale Delle Ricerche, Istituto di Cristallografia, Bari, Italy.

Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder whose patients present mutations in two ribosome assembly proteins, the Shwachman-Bodian-Diamond Syndrome protein (SBDS) and the Elongation Factor-Like 1 (EFL1). Due to the lack of knowledge of the molecular mechanisms responsible for SDS pathogenesis, current therapy is nonspecific and focuses only at alleviating the symptoms. Building on the recent observation that EFL1 single-point mutations clinically manifest as SDS-like phenotype, we carried out comparative Molecular Dynamics (MD) simulations on three mutants, T127A, M882K and R1095Q and wild type EFL1. As supported by small angle X-ray scattering experiments, the obtained data improve the static EFL1 model resulting from the Cryo-electron microscopy and clearly show that all the mutants experience a peculiar rotation, around the hinge region, of domain IV with respect to domains I and II leading to a different conformation respect to that of wild type protein. This study supports the notion that EFL1 function is governed by an allosteric mechanism involving the concerted action of GTPase domain (domain I) and the domain IV and can help point towards new approaches to SDS treatment.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1704883DOI Listing
October 2020

Human ether-à-go-go-related potassium channel: exploring SAR to improve drug design.

Drug Discov Today 2020 02 19;25(2):344-366. Epub 2019 Nov 19.

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona, 4, 70126 Bari, Italy. Electronic address:

hERG is best known as a primary anti-target, the inhibition of which is responsible for serious side effects. A renewed interest in hERG as a desired target, especially in oncology, was sparked because of its role in cellular proliferation and apoptosis. In this study, we survey the most recent advances regarding hERG by focusing on SAR in the attempt to elucidate, at a molecular level, off-target and on-target actions of potential hERG binders, which are highly promiscuous and largely varying in structure. Understanding the rationale behind hERG interactions and the molecular determinants of hERG activity is a real challenge and comprehension of this is of the utmost importance to prioritize compounds in early stages of drug discovery and to minimize cardiotoxicity attrition in preclinical and clinical studies.
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http://dx.doi.org/10.1016/j.drudis.2019.11.005DOI Listing
February 2020

Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors.

Bioorg Chem 2019 12 3;93:103335. Epub 2019 Oct 3.

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, Kerala, India. Electronic address:

The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC value of 0.0021 µM, followed by compounds O10 and O17 (IC = 0.0030 and 0.0034 µM, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC value of 0.029 µM, followed by O3, O4, O9, and O2 (IC = 0.035, 0.053, 0.072, and 0.082 µM, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC value for MAO-B = 0.010 µM) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective K values of 0.016 ± 0.0007 and 0.00050 ± 0.00003 µM. Lead compound are also non-toxic at 200 µg/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data.
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http://dx.doi.org/10.1016/j.bioorg.2019.103335DOI Listing
December 2019

Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer's Disease.

CNS Neurol Disord Drug Targets 2019 ;18(8):643-654

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad-678557, Kerala, India.

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B.

Objectives: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer's Disease (AD).

Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed.

Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively.

Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.
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http://dx.doi.org/10.2174/1871527318666190906101326DOI Listing
October 2020

Accelerating Drug Discovery by Early Protein Drug Target Prediction Based on a Multi-Fingerprint Similarity Search.

Molecules 2019 Jun 14;24(12). Epub 2019 Jun 14.

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy.

In this continuing work, we have updated our recently proposed Multi-fingerprint Similarity Search algorithm (MuSSel) by enabling the generation of dominant ionized species at a physiological pH and the exploration of a larger data domain, which included more than half a million high-quality small molecules extracted from the latest release of ChEMBL (version 24.1, at the time of writing). Provided with a high biological assay confidence score, these selected compounds explored up to 2822 protein drug targets. To improve the data accuracy, samples marked as prodrugs or with equivocal biological annotations were not considered. Notably, MuSSel performances were overall improved by using an object-relational database management system based on PostgreSQL. In order to challenge the real effectiveness of MuSSel in predicting relevant therapeutic drug targets, we analyzed a pool of 36 external bioactive compounds published in the Journal of Medicinal Chemistry from October to December 2018. This study demonstrates that the use of highly curated chemical and biological experimental data on one side, and a powerful multi-fingerprint search algorithm on the other, can be of the utmost importance in addressing the fate of newly conceived small molecules, by strongly reducing the attrition of early phases of drug discovery programs.
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http://dx.doi.org/10.3390/molecules24122233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631269PMC
June 2019

A New Approach for Drug Target and Bioactivity Prediction: The Multifingerprint Similarity Search Algorithm (MuSSeL).

J Chem Inf Model 2019 01 14;59(1):586-596. Epub 2018 Dec 14.

Dipartimento di Farmacia-Scienze del Farmaco , Università degli Studi di Bari "Aldo Moro" , Via E. Orabona, 4 , I-70126 Bari , Italy.

We present MuSSeL, a multifingerprint similarity search algorithm, able to predict putative drug targets for a given query small molecule as well as to return a quantitative assessment of its bioactivity in terms of K or IC values. Predictions are automatically made exploiting a large collection of high quality experimental bioactivity data available from ChEMBL (version 22.1) combining, in a consensus-like approach, predictions resulting from a similarity search performed using 13 different fingerprint definitions. Importantly, the herein proposed algorithm is also effective in detecting and handling activity cliffs. A calibration set including small molecules present in the last updated version of ChEMBL (version 23) was employed to properly tune the algorithm parameters. Three randomly built external sets were instead challenged for model performances. The potential use of MuSSeL was also challenged by a prospective exercise for the prediction of five bioactive compounds taken from articles published in the Journal of Medicinal Chemistry just few months ago. The paper emphasizes the importance of implementing multifingerprint consensus strategies to increase the confidence in prediction of similarity search algorithms and provides a fast and easy-to-run tool for drug target and bioactivity prediction.
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http://dx.doi.org/10.1021/acs.jcim.8b00698DOI Listing
January 2019