scholarly journals Homology Modeling and Virtual Screening Studies of Antigen MLAA-42 Protein: Identification of Novel Drug Candidates against Leukemia—An In Silico Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Ihsan A. Shehadi ◽  
Huda R. M. Rashdan ◽  
Aboubakr H. Abdelmonsef
Keyword(s):  
Virtual Screening ◽  
Homology Modeling ◽  
Protein Identification ◽  
Binding Affinities ◽  
Monocytic Leukemia ◽  
Drug Candidates ◽  
Promising Target ◽  
Leukemia Treatment ◽  
Potent Drug ◽  
Novel Drug

Monocytic leukemia-associated antigen-42 (MLAA-42) is associated with excessive cell division and progression of leukemia. Thus, human MLAA-42 is considered as a promising target for designing of new lead molecules for leukemia treatment. Herein, the 3D model of the target was generated by homology modeling technique. The model was then evaluated using various cheminformatics servers. Moreover, the virtual screening studies were performed to explore the possible binding patterns of ligand molecules to MLAA’s active site pocket. Thirteen ligand molecules from the ChemBank™ database were identified as they showed good binding affinities, scaffold diversity, and preferential ADME properties which may act as potent drug candidates against leukemia. The study provides the way to identify novel therapeutics with optimal efficacy, targeting MLAA-42.

scholarly journals VIRTUAL SCREENING AND IDENTIFICATION OF PLAUSIBLE NOVEL THERAPEUTIC EGFR INHIBITORS AGAINST BREAST CANCER

2021 ◽  
Vol 9 (4) ◽  
pp. 481-491
Author(s):  
Megana KSNM ◽  
◽  
Suneetha Y ◽  
Keyword(s):  
Breast Cancer ◽  
Virtual Screening ◽  
Anticancer Agents ◽  
Docking Studies ◽  
The Novel ◽  
Drug Candidates ◽  
Promising Target ◽  
Toxic Drug ◽  
Screening And Identification ◽  
Novel Drug

Present days increasing concern about the identification of potential non-toxic drug candidates against several cancers is very important. The current study was carried out to discover the novel phytochemicals as effective anticancer agents against the selected protein (i.e., EGFR), which is a promising target for moderating triple-negative breast cancer (TNBC). Various studies showed that the natural constituents have a strong anti-tumor capacity and inhibiting tumor growth. Here structure-based virtual screening and molecular docking studies have been recognized as rational tactics for the recognition of novel drug candidates against the binding domain of EGFR (PDB code: 3GKW & 5FEE). Furthermore, the drug-likeness, adverse effects, and toxicogenomics effects were assessed with the help of various computational tools. Virtual screening was reported that 4 drug candidates i.e., CID: 65064; CID: 5280443; CID: 440735, and CID: 5280343 showed reliable consequences with fewer side effects and more efficient for the selected proteins. The overall effects indicated that renowned hits could be developed as reference skeletons for novel inhibitors envisaging EGFR to ameliorate TNBC.

Introduction of Advanced Methods for Structure-based Drug Discovery

2020 ◽  
Vol 15 ◽  
Author(s):  
Bilal Shaker ◽  
Kha Mong Tran ◽  
Chanjin Jung ◽  
Dokyun Na
Keyword(s):  
Drug Discovery ◽  
Pharmaceutical Industry ◽  
Virtual Screening ◽  
Molecular Basis ◽  
3D Structure ◽  
Protein Targets ◽  
Drug Candidates ◽  
Web Tools ◽  
Conventional Drug ◽  
Potent Drug

: Structure-based drug discovery has become a promising and efficient approach for identifying novel and potent drug candidates with less time and cost than conventional drug discovery approaches. It has been widely used in the pharmaceutical industry since it uses the 3D structure of biological protein targets and thereby to understand the molecular basis of diseases. For the virtual identification of drug candidates based on structure, there are a few steps for protein and compound preparations to obtain accurate results. In this review, the software and web-tools for the preparation and structure-based simulation are introduced. In addition, recent improvements in structure-based virtual screening, target library designing for virtual screening, docking, scoring, and postprocessing of top hits are also introduced.

scholarly journals Drug screening using shape-based virtual screening and in vitro experimental models of cutaneous Leishmaniasis

Parasitology ◽  
2020 ◽  
pp. 1-7
Author(s):  
Camila Cardoso Santos ◽  
Marcos Meuser Batista ◽  
Asma Inam Ullah ◽  
Tummala Rama Krishna Reddy ◽  
Maria de Nazaré Correia Soeiro
Keyword(s):  
Virtual Screening ◽  
Cutaneous Leishmaniasis ◽  
Mucosal Damage ◽  
Peritoneal Macrophages ◽  
Experimental Models ◽  
Drug Candidates ◽  
Non Invasive ◽  
Negative Impacts ◽  
Potent Drug

Abstract Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL. In this sense, we have implemented a shape-based virtual screening approach and identified a set of 32 hit compounds. In vitro phenotypic screenings were conducted using these hit compounds to check their potential leishmanicidal effect towards Leishmania amazonensis (L. amazonensis). Two (Cp1 and Cp2) out of the 32 compounds revealed promising antiparasitic activities, exhibiting considerable potency against intracellular amastigotes present in peritoneal macrophages (IC50 values of 9.35 and 7.25 μm, respectively). Also, a sterile cidality profile was reached at 20 μm after 48 h of incubation, besides a reasonable selectivity (≈8), quite similarly to pentamidine, a diamidine still in use clinically for leishmaniasis. Cp1 with an oxazolo[4,5-b]pyridine scaffold and Cp2 with benzimidazole scaffold could be developed by lead optimization studies to enhance their leishmanicidal potency.

scholarly journals The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

2021 ◽  
Vol 15 (3) ◽  
pp. e0009226
Author(s):  
Hugo R. Vaca ◽  
Ana M. Celentano ◽  
María Agustina Toscanini ◽  
Tino Heimburg ◽  
Ehab Ghazy ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Drug Targets ◽  
Neglected Tropical Diseases ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Positive Interaction ◽  
Drug Candidates ◽  
Larval Stages ◽  
Potent Drug ◽  
Novel Drug

Background Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti). Methodology/Principal findings Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them–entinostat, TH65, and TH92 –had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed. Conclusion, significance The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.

The Research of New Inhibitors of Bacterial Methionine Aminopeptidase by Structure Based Virtual Screening Approach of ZINC DATABASE and In Vitro Validation

2020 ◽  
Vol 16 (4) ◽  
pp. 389-401 ◽  
Author(s):  
Hanane Boucherit ◽  
Abdelouahab Chikhi ◽  
Abderrahmane Bensegueni ◽  
Amina Merzoug ◽  
Jean-Michel Bolla
Keyword(s):  
Virtual Screening ◽  
Bacterial Survival ◽  
Methionine Aminopeptidase ◽  
Bacterial Strains ◽  
Microdilution Method ◽  
Zinc Database ◽  
Promising Target ◽  
New Antibiotics ◽  
Potential Inhibitors

Background: The great emergence of multi-resistant bacterial strains and the low renewal of antibiotics molecules are leading human and veterinary medicine to certain therapeutic impasses. Therefore, there is an urgent need to find new therapeutic alternatives including new molecules in the current treatments of infectious diseases. Methionine aminopeptidase (MetAP) is a promising target for developing new antibiotics because it is essential for bacterial survival. Objective: To screen for potential MetAP inhibitors by in silico virtual screening of the ZINC database and evaluate the best potential lead molecules by in vitro studies. Methods: We have considered 200,000 compounds from the ZINC database for virtual screening with FlexX software to identify potential inhibitors against bacterial MetAP. Nine chemical compounds of the top hits predicted were purchased and evaluated in vitro. The antimicrobial activity of each inhibitor of MetAP was tested by the disc-diffusion assay against one Gram-positive (Staphylococcus aureus) and two Gram-negative (Escherichia coli & Pseudomonas aeruginosa) bacteria. Among the studied compounds, compounds ZINC04785369 and ZINC03307916 showed promising antibacterial activity. To further characterize their efficacy, the minimum inhibitory concentration was determined for each compound by the microdilution method which showed significant results. Results: These results suggest compounds ZINC04785369 and ZINC03307916 as promising molecules for developing MetAP inhibitors. Conclusion: Furthermore, they could therefore serve as lead molecules for further chemical modifications to obtain clinically useful antibacterial agents.

scholarly journals Novel Method for Quantifying AhR-Ligand Binding Affinities Using Microscale Thermophoresis

Biosensors ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 60
Author(s):  
Anne Stinn ◽  
Jens Furkert ◽  
Stefan H. E. Kaufmann ◽  
Pedro Moura-Alves ◽  
Michael Kolbe
Keyword(s):  
Ligand Binding ◽  
Environmental Pollutants ◽  
Screening Strategy ◽  
Pharmacological Intervention ◽  
Binding Affinities ◽  
Free System ◽  
Microscale Thermophoresis ◽  
Aryl Hydrocarbon ◽  
Promising Target ◽  
A Cell

The aryl hydrocarbon receptor (AhR) is a highly conserved cellular sensor of a variety of environmental pollutants and dietary-, cell- and microbiota-derived metabolites with important roles in fundamental biological processes. Deregulation of the AhR pathway is implicated in several diseases, including autoimmune diseases and cancer, rendering AhR a promising target for drug development and host-directed therapy. The pharmacological intervention of AhR processes requires detailed information about the ligand binding properties to allow specific targeting of a particular signaling process without affecting the remaining. Here, we present a novel microscale thermophoresis-based approach to monitoring the binding of purified recombinant human AhR to its natural ligands in a cell-free system. This approach facilitates a precise identification and characterization of unknown AhR ligands and represents a screening strategy for the discovery of potential selective AhR modulators.

scholarly journals Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pusheng Quan ◽  
Kai Wang ◽  
Shi Yan ◽  
Shirong Wen ◽  
Chengqun Wei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Target ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Control Group ◽  
Drug Candidates ◽  
Novel Drug

AbstractThis study aimed to identify potential novel drug candidates and targets for Parkinson’s disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

scholarly journals Missing Novelty in Drug Development

2021 ◽  
Author(s):  
Joshua Krieger ◽  
Danielle Li ◽  
Dimitris Papanikolaou
Keyword(s):  
Radical Innovation ◽  
Chemical Similarity ◽  
Net Worth ◽  
Drug Candidates ◽  
Pharmaceutical Firms ◽  
External Finance ◽  
Fda Approval ◽  
Novel Drugs ◽  
Positive Shock ◽  
Novel Drug

Abstract We provide evidence that risk aversion leads pharmaceutical firms to underinvest in radical innovation. We introduce a new measure of drug novelty based on chemical similarity and show that firms face a risk-reward trade-off: novel drug candidates are less likely to obtain FDA approval but are based on more valuable patents. Consistent with a simple model of costly external finance, we show that a positive shock to firms’ net worth leads firms to develop more novel drugs. This suggests that even large firms may behave as though they are risk averse, reducing their willingness to investment in potentially valuable radical innovation.

Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective

2015 ◽  
Vol 309 (12) ◽  
pp. F996-F999 ◽  
Author(s):  
James A. Shayman
Keyword(s):  
Drug Targets ◽  
Lysosomal Storage ◽  
Federal Drug Administration ◽  
Drug Candidates ◽  
Gaucher Disease Type 1 ◽  
Biotechnology Companies ◽  
Approved Drugs ◽  
Novel Drug ◽  
Early Drug

Historically, most Federal Drug Administration-approved drugs were the result of “in-house” efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1.

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