scholarly journals Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2326
Author(s):  
Tahani M. Almeleebia ◽  
Mesfer Al Shahrani ◽  
Mohammad Y. Alshahrani ◽  
Irfan Ahmad ◽  
Abdullah M. Alkahtani ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Proteasome Inhibitors ◽  
Computational Prediction ◽  
Amino Acid Residues ◽  
Reference Compound ◽  
Knowledge Based ◽  
Computational Screening ◽  
Zinc Database ◽  
Property Assessment ◽  
Potential Inhibitors

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of −7.19, −7.95, and −7.21 kcal/mol for the monomer (K-chain) and −8.05, −9.10, and −7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (−5.83 kcal/mol (monomer) and −5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome.

scholarly journals Erratum to: Discovery of new Mycobacterium tuberculosis proteasome inhibitors using a knowledge-based computational screening approach

2015 ◽  
Vol 20 (1) ◽  
pp. 367-367 ◽  
Author(s):  
Rukmankesh Mehra ◽  
Reena Chib ◽  
Gurunadham Munagala ◽  
Kushalava Reddy Yempalla ◽  
Inshad Ali Khan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Proteasome Inhibitors ◽  
Knowledge Based ◽  
Computational Screening ◽  
Screening Approach

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 Functional Analysis of the Mycobacterium tuberculosis FAD-Dependent Thymidylate Synthase, ThyX, Reveals New Amino Acid Residues Contributing to an Extended ThyX Motif

2008 ◽  
Vol 190 (6) ◽  
pp. 2056-2064 ◽  
Author(s):  
Jonathan E. Ulmer ◽  
Yap Boum ◽  
Christopher D. Thouvenel ◽  
Hannu Myllykallio ◽  
Carol Hopkins Sibley
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Thymidylate Synthase ◽  
Three Dimensional ◽  
Pyrimidine Ring ◽  
Dimensional Structure ◽  
Directed Mutagenesis ◽  
Catalytic Residue ◽  
Amino Acid Residues ◽  
Insight Into

ABSTRACT A novel FAD-dependent thymidylate synthase, ThyX, is present in a variety of eubacteria and archaea, including the mycobacteria. A short motif found in all thyX genes, RHRX7-8S, has been identified. The three-dimensional structure of the Mycobacterium tuberculosis ThyX enzyme has been solved. Building upon this information, we used directed mutagenesis to produce 67 mutants of the M. tuberculosis thyX gene. Each enzyme was assayed to determine its ability to complement the defect in thymidine biosynthesis in a ΔthyA strain of Escherichia coli. Enzymes from selected strains were then tested in vitro for their ability to catalyze the oxidation of NADPH and the release of a proton from position 5 of the pyrimidine ring of dUMP. The results defined an extended motif of amino acids essential to enzyme activity in M. tuberculosis (Y44X24 H69X25R95HRX7 S105XRYX90R199 [with the underlined histidine acting as the catalytic residue and the underlined serine as the nucleophile]) and provided insight into the ThyX reaction mechanism. ThyX is found in a variety of bacterial pathogens but is absent in humans, which depend upon an unrelated thymidylate synthase, ThyA. Therefore, ThyX is a potential target for development of antibacterial drugs.

scholarly journals Materials Precursor Score: Modelling Chemists' Intuition for the Synthetic Accessibility of Porous Organic Cages

2021 ◽  
Author(s):  
Steven Bennett ◽  
Filip Szczypiński ◽  
Lukas Turcani ◽  
Michael Briggs ◽  
Rebecca L. Greenaway ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Class Imbalance ◽  
Computational Prediction ◽  
Material Development ◽  
Computational Screening ◽  
Machine Learning Model ◽  
Synthetic Accessibility ◽  
Internal Cavities ◽  
Computational Discovery ◽  
Novel Structures

<div>Computation is increasingly being used to try to accelerate the discovery of new materials. One specific example of this is porous molecular materials, specifically porous organic cages, where the porosity of the materials predominantly comes from the internal cavities of the molecules themselves. The computational discovery of novel structures with useful properties is currently hindered by the difficulty in transitioning from a computational prediction to synthetic realisation. Attempts at experimental validation are often time-consuming, expensive and, frequently, the key bottleneck of material discovery. In this work, we developed a computational screening workflow for porous molecules that includes consideration of the synthetic difficulty of material precursors, aimed at easing the transition between computational prediction and experimental realisation. We trained a machine learning model by first collecting data on 12,553 molecules categorised either as `easy-to-synthesise' or `difficult-to-synthesise' by expert chemists with years of experience in organic synthesis. We used an approach to address the class imbalance present in our dataset, producing a binary classifier able to categorise easy-to-synthesise molecules with few false positives. We then used our model during computational screening for porous organic molecules to bias towards precursors whose easier synthesis requirements would make them promising candidates for experimental realisation and material development. We found that even by limiting precursors to those that are easier-to-synthesise, we are still able to identify cages with favourable, and even some rare, properties. </div>

scholarly journals Structure-based virtual screening for new lead compounds targeted Plasmodium α-tubulin

2021 ◽  
Vol 28 ◽  
pp. 135-139
Author(s):  
O. V. Rayevsky ◽  
O. M. Demchyk ◽  
P. A. Karpov ◽  
S. P. Ozheredov ◽  
S. I. Spivak ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Protein Interaction ◽  
Specific Binding ◽  
Pharmacophore Model ◽  
Computational Prediction ◽  
Mitotic Apparatus ◽  
Ligand Interaction ◽  
Lead Compounds ◽  
Key Functional Groups ◽  
Potential Inhibitors

Aim. Search for new dinitroaniline and phosphorothioamide compounds, capable of selective binding with Plasmodium α-tubulin, affecting its mitotic apparatus. Methods. Structural biology methods of computational prediction of protein-ligand interaction: molecular docking, molecular dynamics and pharmacophore analysis. Selection of compounds based on pharmacophore characteristics and virtual screening results. Results. The protocol and required structural conditions for target (α-tubulin of P. falciparum) preparation and correct modeling of the ligand-protein interaction (docking and virtual screening) were developed. The generalized pharmacophore model of ligand-protein interaction and key functional groups of ligands responsible for specific binding were identified. Conclusions. Based on results of virtual screening, 22 commercial compounds were selected. Identified compounds proposed as potential inhibitors of Plasmodium mitotic machinery and the base of new antimalarial drugs. Keywords: malaria, Plasmodium, intermolecular interaction, dinitroaniline derived, phosphorothioamidate derived.

scholarly journals A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

2020 ◽  
Vol 7 ◽  
Author(s):  
Rounak Chourasia ◽  
Srichandan Padhi ◽  
Loreni Chiring Phukon ◽  
Md Minhajul Abedin ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Drug Targets ◽  
Docking Studies ◽  
Lactobacillus Delbrueckii ◽  
Amino Acid Residues ◽  
Main Protease ◽  
Effective Inhibition ◽  
Cheese Peptides ◽  
Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

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