Pharmacophore-Guided Identification of Natural Products as Potential Inhibitors of Mycobacterium ulcerans Cystathionine γ-Synthase MetB

Buruli ulcer caused by Mycobacterium ulcerans (M. ulcerans) is identified by a pain-free cyst or edema which develops into a massive skin ulcer if left untreated. There are reports of chemoresistance, toxicity, noncompliance, and poor efficacy of current therapeutic options. Previously, we used cheminformatics approaches to identify potential antimycobacterial compounds targeting major receptors in M. ulcerans. In this paper, we sought to identify potential bioactive compounds by targeting Cystathionine gamma-synthase (CGS) MetB, a key receptor involved in methionine synthesis. Inhibition of methionine synthesis restricts the growth of M. ulcerans. Two potent inhibitors Juglone (IC50 0.7 +/− 0.7 µmol/L) and 9-hydroxy-alpha-lapachone (IC50 0.9 +/− 0.1 µmol/L) were used to generate 3D chemical feature pharmacophore model via LigandScout with a score of 0.9719. The validated model was screened against a pre-filtered library of 2530 African natural products. Compounds with fit scores above 66.40 were docked against the structure of CGS to generate hits. Three compounds, namely Gentisic 5-O glucoside (an isolate of African tree Alchornea cordifolia), Isoscutellarein (an isolate of Theobroma plant) and ZINC05854400, were identified as potential bioactive molecules with high binding affinities of −7.1, −8.4 and −8.4 kcal/mol against CGS, respectively. Novel structural insight into the binding mechanisms was elucidated using LigPlot+ and molecular dynamics simulations. All three molecules were predicted to possess antibacterial, anti-ulcerative, and dermatological properties. These compounds have the propensity to disrupt the methionine synthesis mechanisms with the potential of stagnating the growth of M. ulcerans. As a result of reasonably good pharmacological profiling, the three drug-like compounds are potential novel scaffolds that can be optimized into antimycobacterial molecules.

Download Full-text

Potential Inhibitors of Fascin From A Database of Marine Natural Products: A Virtual Screening and Molecular Dynamics Study

Frontiers in Chemistry ◽

10.3389/fchem.2021.719949 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lirui Lin ◽

Kai Lin ◽

Xiaodong Wu ◽

Jia Liu ◽

Yinwei Cheng ◽

...

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Virtual Screening ◽

Marine Natural Products ◽

Pharmacophore Model ◽

Binding Affinities ◽

Dynamic Interactions ◽

Generalized Born ◽

Accelerated Molecular Dynamics ◽

Potential Inhibitors

Marine nature products are unique compounds that are produced by the marine environment including plants, animals, and microorganisms. The wide diversity of marine natural products have great potential and are versatile in terms of drug discovery. In this paper, we use state-of-the-art computational methods to discover inhibitors from marine natural products to block the function of Fascin, an overexpressed protein in various cancers. First, virtual screening (pharmacophore model and molecular docking) was carried out based on a marine natural products database (12015 molecules) and provided eighteen molecules that could potentially inhibit the function of Fascin. Next, molecular mechanics generalized Born surface area (MM/GBSA) calculations were conducted and indicated that four molecules have higher binding affinities than the inhibitor NP-G2-029, which was validated experimentally. ADMET analyses of pharmacokinetics demonstrated that one of the four molecules does not match the criterion. Finally, ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations were carried out to validate the three inhibitors binding to Fascin stably. In addition, dynamic interactions between protein and ligands were analyzed systematically. Our study will accelerate the development of the cancer drugs targeting Fascin.

Download Full-text

Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

Microorganisms ◽

10.3390/microorganisms8070970 ◽

2020 ◽

Vol 8 (7) ◽

pp. 970 ◽

Cited By ~ 4

Author(s):

Ahmed M. Sayed ◽

Hani A. Alhadrami ◽

Ahmed O. El-Gendy ◽

Yara I. Shamikh ◽

Lassaad Belbahri ◽

...

Keyword(s):

Natural Products ◽

Protein Complexes ◽

Binding Free Energy ◽

Binding Affinities ◽

Binding Modes ◽

Drug Candidates ◽

Main Protease ◽

Potential Inhibitors ◽

Microbial Natural Products

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.

Download Full-text

Identification of Potential inhibitors for Hematopoietic Prostaglandin D2 Synthase: Computational Modeling and Molecular Dynamics Simulations

10.1101/2021.08.19.456954 ◽

2021 ◽

Author(s):

Satyajit Beura ◽

Prabhakar Chetti

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Virtual Screening ◽

Molecular Dynamics Simulations ◽

Binding Free Energy ◽

Pharmacophore Model ◽

Prostaglandin D2 ◽

Prostaglandin D2 Synthase ◽

Dynamics Simulations ◽

Potential Inhibitors

To design a new therapeutic agent for Hematopoietic Prostaglandin D2 synthase (hPGDS), a set of 60 molecules with different molecular scaffolds were (range of pIC50 values are from 8.301 to 3.932) considered to create a pharmacophore model. Further, identification of potential hPGDS inhibitors were carried out by using virtual screening with different databases (from 15,74,182 molecules). The Molecular screening was performed using different sequential methods right from Pharmacophore based virtual screening, molecular docking, MM-GBSAstudies, ADME property analysis and molecular dynamics simulations using Maestro11.9 software. Based on the best pharmacophore model (ADRR_1), the resultant set of 18,492 molecules were screened. The preliminarily screened molecules were subjected to molecular docking (PDB_ID: 2CVD) methods. A set of 27 molecules was screened from the resultant molecular docking outcomes (360 molecules) based on binding free energy (ΔGbind) and Lipinskis rule of five. Out of 27 molecules, 4 were selected visual data analysis and further subjected to molecular dynamics (MD) simulation study. Outcomes of the present study conclude with three new proposed molecules (SP1, SP2 and SP10) which show a good range of interaction with human hPGDS enzyme in comparison to the marketed compounds i.e., HQL-79, TFC-007, HPGDS inhibitor I and TAS-204.

Download Full-text

Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0248 ◽

2021 ◽

Author(s):

Jurica Novak ◽

Hrvoje Rimac ◽

Shivananda Kandagalla ◽

Maria A Grishina ◽

Vladimir A Potemkin

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Virtual Screening ◽

Molecular Dynamics Simulations ◽

Natural Product ◽

Binding Sites ◽

Potent Inhibitor ◽

Maturation Process ◽

Dynamics Simulations ◽

Potential Inhibitors

Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.

Download Full-text

Mechanism of Mycolactone Toxin Membrane Permeation: Atomistic vs Coarse-Grained MARTINI Simulations

10.1101/470807 ◽

2018 ◽

Author(s):

F. Aydin ◽

R. Sun ◽

J. M. J. Swanson

Keyword(s):

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Coarse Grained ◽

Membrane Permeation ◽

Lipid Trafficking ◽

Ulcer Disease ◽

Cellular Processes ◽

Coarse Grained Simulations ◽

Dynamics Simulations

ABSTRACTMycolactone, a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans, is the central virulent factor in the skin disease Buruli ulcer. This multifunctional cytotoxin affects fundamental cellular processes such as cell adhesion, immune response and cell death by targeting various cellular structures. Developing effective diagnostics that target mycolactone has been challenging, potentially due to suspected interactions with lipophilic architectures, including membranes. To better understand the pathogenesis of Buruli ulcer disease, aid in the development of diagnostics, and learn how amphiphiles in general use lipid trafficking to navigate the host environment, we seek to understand the nature of mycolactone-membrane interactions. Herein we characterize how the two dominant isomers of mycolactone (A and B) interact with and permeate DPPC membranes with all-atom molecular dynamics simulations employing transition tempered metadynamics, and compare these results with those obtained by MARTINI coarse-grained simulations. Our all-atom simulations reveal that both isomers have a strong preference to associate with the membrane, although their mechanisms and energetics of membrane permeation differ slightly. Water molecules are found to play an important role in the permeation process. Although the MARTINI coarse-grained simulations give the correct free energy of membrane association, they fail to capture the mechanism of permeation and role of water during permeation as seen in all-atom simulations.

Download Full-text

Bioactive Molecules of Tea as Potential Inhibitors for RNA-Dependent RNA Polymerase of SARS-CoV-2

Frontiers in Medicine ◽

10.3389/fmed.2021.684020 ◽

2021 ◽

Vol 8 ◽

Author(s):

Vijay Kumar Bhardwaj ◽

Rahul Singh ◽

Jatin Sharma ◽

Vidya Rajendran ◽

Rituraj Purohit ◽

...

Keyword(s):

Rna Polymerase ◽

Drug Repurposing ◽

Docking Studies ◽

Antiviral Drugs ◽

Bioactive Molecules ◽

Rna Dependent Rna Polymerase ◽

Dynamics Simulations ◽

Potential Inhibitors

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus. The enzyme RNA-dependent RNA polymerase (RdRp) performs a pivotal role in replicating the virus. RdRp is a prime target for Remdesivir and other nucleotides analog-based antiviral drugs. In this study, we showed three bioactive molecules from tea (epicatechin-3,5-di-O-gallate, epigallocatechin-3,5-di-O-gallate, and epigallocatechin-3,4-di-O-gallate) that showed better interaction with critical residues present at the catalytic center and the NTP entry channel of RdRp than antiviral drugs Remdesivir and Favipiravir. Our computational approach to identify these molecules included molecular docking studies, followed by robust molecular dynamics simulations. All the three molecules are readily available in tea and could be made accessible along with other medications to treat COVID-19 patients. However, these results require validation by further in vitro and in vivo studies.

Download Full-text

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

International Journal of Molecular Sciences ◽

10.3390/ijms22105311 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5311

Author(s):

Shraddha Parate ◽

Vikas Kumar ◽

Danishuddin ◽

Jong Chan Hong ◽

Keun Woo Lee

Keyword(s):

Small Molecule ◽

Pharmacophore Model ◽

Cancer Therapeutics ◽

Binding Affinities ◽

Free Energies ◽

Docking Analysis ◽

Complex Interactions ◽

Pharmacophore Generation ◽

Dynamics Simulations ◽

Binding Free Energies

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.

Download Full-text

Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies

Current Bioactive Compounds ◽

10.2174/1573407213666170828165512 ◽

2019 ◽

Vol 15 (2) ◽

pp. 257-267 ◽

Cited By ~ 3

Author(s):

Paritosh Shukla ◽

Ashok Sharma ◽

Leena Fageria ◽

Rajdeep Chowdhury

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

In Silico ◽

Antimicrobial Agents ◽

Docking Studies ◽

Bioactive Molecules ◽

Microwave Assisted Synthesis ◽

Binding Affinities ◽

In Silico Docking

Background: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.

Download Full-text

Interactions between ecological and socio-economic drivers of Buruli ulcer burden in Sub-Saharan Africa: opportunities for an improved control

10.1093/oso/9780198789833.003.0014 ◽

2018 ◽

Author(s):

Andes Garchitorena ◽

Matthew H. Bonds ◽

Jean-Francois Guégan ◽

Benjamin Roche

Keyword(s):

Socioeconomic Factors ◽

Disease Transmission ◽

Access To Health Care ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Sub Saharan Africa ◽

Aquatic Environments ◽

Human Populations ◽

Complex Interactions ◽

Sub Saharan

This chapter provides an overview of the complex interactions between ecological and socioeconomic factors for the development and control of Buruli ulcer in Sub-Saharan Africa. We review key ecological and evolutionary processes driving the environmental persistence and proliferation of Mycobacterium ulcerans, the causative agent, within aquatic environments, as well as transmission processes from these aquatic environments to human populations. We also outline key socioeconomic factors driving the economic and health burden of Buruli ulcer in endemic regions, revealed by reciprocal feedbacks between poverty, disease transmission from exposure aquatic environments and disease progression to severe stages owing to low access to health care. The implications of such insights for disease control, both in terms of limitations of current strategies and directions for the future, are discussed.

Download Full-text