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Article ; Online: Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method.

Martorana, Annamaria / Lauria, Antonino

Journal of molecular graphics & modelling

2020 Volume 100, Page(s) 107666

Abstract: An important challenge, in the medicinal chemistry field, is the research of novel forceful drugs to overcome tumor-acquired resistance. The c-Kit tyrosine kinase receptor (TKR) represents a suitable target for the carcinogenesis control of gastro- ... ...

Abstract	An important challenge, in the medicinal chemistry field, is the research of novel forceful drugs to overcome tumor-acquired resistance. The c-Kit tyrosine kinase receptor (TKR) represents a suitable target for the carcinogenesis control of gastro-intestinal stromal (GIST), leukemia, and mastocytosis tumors; nevertheless, several hotspot mutations of the protein limit the efficacy of a few clinical administered TKRs inhibitors. In this study, a new in silico protocol based on ligand and structure-based combined method is proposed, with the aim to identify a set of new c-Kit inhibitors able to complex c-Kit mutated proteins. A recent and freely available web-server DRUDIT is used for the ligand-based method. The protocol application allows for identifying a new generation of potential TKR inhibitors, which, in silico, complex the V654A and T670I mutated proteins and potentially overcome resistant mutations (D816H). The structure-based analysis is performed by Induced Fit Docking (IFD) studies. The comparison between the explored ligands and well-known drugs highlights the possibility to overcome tumor-acquired resistance. The best-selected structures (630705 and SML1348) provide valuable binding affinities with the mutated c-Kit forms (respectively T670I and V654A).
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Resistance, Neoplasm ; Gastrointestinal Stromal Tumors/drug therapy ; Humans ; Ligands ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-kit/genetics
Chemical Substances	Antineoplastic Agents ; Ligands ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1396450-1
ISSN	1873-4243 ; 1093-3263
ISSN (online)	1873-4243
ISSN	1093-3263
DOI	10.1016/j.jmgm.2020.107666
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Article ; Online: Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives.

La Monica, Gabriele / Bono, Alessia / Lauria, Antonino / Martorana, Annamaria

Journal of medicinal chemistry

2022 Volume 65, Issue 19, Page(s) 12500–12534

Abstract: The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the ... ...

Abstract	The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Coronavirus 3C Proteases ; Cysteine ; Cysteine Endopeptidases/metabolism ; Humans ; Molecular Docking Simulation ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protease Inhibitors/therapeutic use ; SARS-CoV-2 ; Structure-Activity Relationship ; Viral Nonstructural Proteins ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Protease Inhibitors ; Viral Nonstructural Proteins ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2022-09-28
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01005
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Article ; Online: In Silico Design of New Dual Inhibitors of SARS-CoV-2 M

Bono, Alessia / Lauria, Antonino / La Monica, Gabriele / Alamia, Federica / Mingoia, Francesco / Martorana, Annamaria

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating ... ...

Abstract	The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series' of small molecules with a significant affinity for SARS-CoV-2 M
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; COVID-19 ; Antiviral Agents/chemistry ; Ligands ; Protease Inhibitors/chemistry ; Molecular Docking Simulation ; Molecular Dynamics Simulation
Chemical Substances	Antiviral Agents ; Ligands ; Protease Inhibitors
Language	English
Publishing date	2023-05-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24098377
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection.

Martorana, Annamaria / Gentile, Carla / Lauria, Antonino

Viruses

2020 Volume 12, Issue 8

Abstract: COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, ... ...

Abstract	COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (M
MeSH term(s)	Aging/metabolism ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/enzymology ; Binding Sites ; Computer Simulation ; Coronavirus Infections/drug therapy ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Cysteine Endopeptidases/chemistry ; DNA Damage ; Drug Repositioning ; HIV Protease Inhibitors/chemistry ; HIV Protease Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Docking Simulation ; NAD/metabolism ; Oxidation-Reduction ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/virology ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry
Chemical Substances	Antiviral Agents ; HIV Protease Inhibitors ; Protease Inhibitors ; Viral Nonstructural Proteins ; NAD (0U46U6E8UK) ; 3C-like proteinase, Coronavirus (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-)
Keywords	covid19
Language	English
Publishing date	2020-07-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12080805
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways.

Martorana, Annamaria / La Monica, Gabriele / Lauria, Antonino

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 18

Abstract: The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, ... ...

Abstract	The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand-protein interactions of the reviewed molecules are summarized.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Cell Survival/drug effects ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Humans ; Molecular Dynamics Simulation ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/metabolism ; Quinolines/chemistry ; Quinolines/metabolism ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Quinolines ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2020-09-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25184279
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Article: In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection

Martorana, Annamaria / Gentile, Carla / Lauria, Antonino

Viruses. 2020 July 26, v. 12, no. 8

2020

Abstract	COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (Mᴾᴿᴼ) inhibitors that fit in the catalytic binding site of SARS CoV-2 Mᴾᴿᴼ. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis.
Keywords	COVID-19 infection ; DNA repair ; Human immunodeficiency virus ; NAD (coenzyme) ; antiviral agents ; binding sites ; catalytic activity ; computer simulation ; databases ; elderly ; metabolism ; molecular models ; oxidative stress ; pandemic ; proteinases
Language	English
Dates of publication	2020-0726
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12080805
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors.

La Monica, Gabriele / Lauria, Antonino / Bono, Alessia / Martorana, Annamaria

International journal of molecular sciences

2021 Volume 22, Issue 11

Abstract: The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong ... ...

Abstract	The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with "secondary" targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions.
MeSH term(s)	Catalytic Domain ; Computer Simulation ; Drug Design ; Drug Discovery ; HIV Infections/drug therapy ; HIV Infections/enzymology ; HIV Infections/virology ; HIV Protease/chemistry ; HIV Protease Inhibitors/pharmacology ; HIV-1/drug effects ; HIV-1/enzymology ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Structure ; Protein Conformation ; Structure-Activity Relationship
Chemical Substances	HIV Protease Inhibitors ; Ligands ; HIV Protease (EC 3.4.23.-)
Language	English
Publishing date	2021-06-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22116070
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Article ; Online: Quinoline anticancer agents active on DNA and DNA-interacting proteins: From classical to emerging therapeutic targets.

Lauria, Antonino / La Monica, Gabriele / Bono, Alessia / Martorana, Annamaria

European journal of medicinal chemistry

2021 Volume 220, Page(s) 113555

Abstract: Quinoline is one of the most important and versatile nitrogen heterocycles embodied in several biologically active molecules. Within the numerous quinolines developed as antiproliferative agents, this review is focused on compounds interfering with DNA ... ...

Abstract	Quinoline is one of the most important and versatile nitrogen heterocycles embodied in several biologically active molecules. Within the numerous quinolines developed as antiproliferative agents, this review is focused on compounds interfering with DNA structure or with proteins/enzymes involved in the regulation of double helix functional processes. In this light, a special focus is given to the quinoline compounds, acting with classical/well-known mechanisms of action (DNA intercalators or Topoisomerase inhibitors). In particular, the quinoline drugs amsacrine and camptothecin (CPT) have been studied as key lead compounds for the development of new agents with improved PK and tolerability properties. Moreover, notable attention has been paid to the quinoline molecules, which are able to interfere with emerging targets involved in cancer progression, as G-quadruplexes or the epigenetic ones (e.g.: histone deacetylase, DNA and histones methyltransferase). The antiproliferative and the enzymatic inhibition data of the reviewed compounds have been analyzed. Furthermore, concerning the SAR (structure-activity relationship) aspects, the most recurrent ligand-protein interactions are summarized, underling the structural requirements for each kind of mechanism of action.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; DNA, Neoplasm/drug effects ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/metabolism ; G-Quadruplexes/drug effects ; Humans ; Molecular Structure ; Quinolines/chemistry ; Quinolines/pharmacology
Chemical Substances	Antineoplastic Agents ; DNA, Neoplasm ; DNA-Binding Proteins ; Quinolines ; quinoline (E66400VT9R)
Language	English
Publishing date	2021-05-24
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2021.113555
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Article ; Online: Design and Synthesis of Novel Thieno[3,2-

La Monica, Gabriele / Pizzolanti, Giuseppe / Baiamonte, Concetta / Bono, Alessia / Alamia, Federica / Mingoia, Francesco / Lauria, Antonino / Martorana, Annamaria

ACS omega

2023 Volume 8, Issue 38, Page(s) 34640–34649

Abstract: RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. ...

Abstract	RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDIT
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c03578
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Correction to "Design and Synthesis of Novel Thieno[3,2-

La Monica, Gabriele / Pizzolanti, Giuseppe / Baiamonte, Concetta / Bono, Alessia / Alamia, Federica / Mingoia, Francesco / Lauria, Antonino / Martorana, Annamaria

ACS omega

2023 Volume 8, Issue 50, Page(s) 48582

Abstract: This corrects the article DOI: 10.1021/acsomega.3c03578.]. ...

Abstract	[This corrects the article DOI: 10.1021/acsomega.3c03578.].
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Published Erratum
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c08743
Database	MEDical Literature Analysis and Retrieval System OnLINE

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