scholarly journals Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya

2018 ◽  
Vol 16 (1) ◽  
pp. 8-21
Author(s):  
MANYIM SCOLASTICA ◽  
ALBERT J. NDAKALA ◽  
SOLOMON DERESE
Keyword(s):  
Natural Products ◽  
Drug Design ◽  
Active Site ◽  
Docking Studies ◽  
Moderate Activity ◽  
Vigorous Activity ◽  
Structure Based Drug Design ◽  
Web Based ◽  
Ic50 Values ◽  
Accessible Form

Scolastica M, Ndakala AJ, Derese S. 2018. Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya. Biofarmasi J Nat Prod Biochem 16: 8-21. Despite numerous research that has been done on plants of Kenya resulting in the isolation of thousands of natural products, data on these natural products are not systematically organized in a readily accessible form. This has urged the construction of a web-based database of natural products of Kenya. The database is named Mitishamba and is hosted at http://mitishamba.uonbi.ac.ke. The Mitishamba database was queried for chromones, chromanones, and chalcones that were subjected to structure-based drug design using Fred (OpenEye) docking utility program with 1TV5 PDB structure of the PfDHODH receptor to identify complex of ligands that bind with the active site. Ligand-based drug design (Shape and electrostatics comparison) was also done on the ligands against query A77 1726 (38) (the ligand that co-crystallized with PfDHODH receptor) using ROCS and EON programs, respectively, of OpenEye suite. There was a substantial similarity among the top performing ligands in the docking studies with shape and electrostatic comparison that led to the identification of compounds of interest which were targeted for synthesis and antiplasmodial assay. In this study, a chromanone (7-hydroxy-2-(4-methoxyphenyl) chroman-4-one (48)) and two intermediate chalcones (2',4'-dihydroxy-4-methoxychalcone (45) and 2’,4’-dihydroxy-4-chlorochalcone (47)), were synthesized and subjected to antiplasmodial assay. Among these substances, 45 showed vigorous activity, whereas 47 and 48 had moderate activity against the chloroquine resistant K1 strain of P. falciparum with IC50 values of 4.56±1.66, 17.62 ± 5.94 and 18.01 ±1.66 µg/ml, respectively. Since the synthesized compounds showed antiplasmodial potential, there is a need for further computational refinement of these compounds to optimize their antiplasmodial activity.

scholarly journals Design of Novel Bioisosteres of β-Diketo Acid Inhibitors of HIV-1 Integrase

2005 ◽  
Vol 16 (1) ◽  
pp. 41-61 ◽  
Author(s):  
Mario Sechi ◽  
Luciano Sannia ◽  
Fabrizio Carta ◽  
Michele Palomba ◽  
Roberto Dallocchio ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Carboxylic Acids ◽  
Active Site ◽  
Docking Studies ◽  
Design Strategies ◽  
Structure Based Drug Design ◽  
Computational Docking ◽  
Lead Compounds ◽  
Hiv 1

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of β-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

2016 ◽  
pp. 196-219
Author(s):  
Sanchaita Rajkhowa ◽  
Ramesh C. Deka
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Drug Design ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Stable Complex ◽  
Scoring Functions ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

The Complex of a Bivalent Derivative of Galanthamine withTorpedoAcetylcholinesterase Displays Drastic Deformation of the Active-Site Gorge:  Implications for Structure-Based Drug Design

2004 ◽  
Vol 126 (47) ◽  
pp. 15405-15411 ◽  
Author(s):  
Harry M. Greenblatt ◽  
Catherine Guillou ◽  
Daniel Guénard ◽  
Anat Argaman ◽  
Simone Botti ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Structure Based Drug Design

scholarly journals Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice Douangamath ◽  
Daren Fearon ◽  
Paul Gehrtz ◽  
Tobias Krojer ◽  
Petra Lukacik ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Design ◽  
Active Site ◽  
Large Scale ◽  
Structure Based Drug Design ◽  
Dimer Interface ◽  
X Ray ◽  
Fragment Screening ◽  
Viral Proteases ◽  
Main Protease

Abstract COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

scholarly journals PHARMACOPHORIC SCREENING OF VARIOUS ENDOPHYTIC FUNGAL METABOLITES

2017 ◽  
Vol 10 (5) ◽  
pp. 140
Author(s):  
Brindha Devi ◽  
Rajagopala K ◽  
Esther Elizabeth
Keyword(s):  
Drug Design ◽  
Pharmacophore Model ◽  
Antioxidant Property ◽  
Docking Studies ◽  
Fungal Metabolites ◽  
Kcal Mole ◽  
Structure Based Drug Design ◽  
Docking Score ◽  
Drug Candidates ◽  
Anti Inflammatory

Objective: To screen various endophytic fungal metabolites toward anti-inflammatory, anticancer, and antioxidant property virtually.Methods: In this study, 14 bioactive compounds reported from endophytic fungi have taken for structure-based drug design. With the help of softwareSchrodinger, different modules were used to perform screening of top active compounds. Ligprep, epharm, Glide, Quikprop are the modules were used from the software for our study. Identification of leads, pharmacophore model generation, and molecular docking studies were assessed using this software.Results: After the screening of molecules virtually, the most bioactive anti-inflammatory compound was found to be cycloepoxytriol with the dockingscore of −7.511 kcal/mole, and the most active anticancer compound was found to be Phomol with the docking score of −9.778 kcal/mole. The mostactive antioxidant compound was found to be Phomol with the docking score of −9.970 kcal/mole. Further account the potential of the compoundsto act as efficient drug candidates, their absorption, distribution, metabolism, and excretion properties were also predicted. All the compounds wereshown to correlate well with all properties virtually.Conclusion: In conclusion, using structure-based drug design, we have obtained some promising leads for anti-inflammatory, anticancer, andantioxidant drug discovery. The discovery of compounds from natural products is very potent for formulating new drugs.Keywords: Endophytes, Anti-inflammatory, Anticancer, Antioxidant, Absorption; distribution; metabolism and excretion.

Combining Dyad Protonation and Active Site Plasticity in BACE-1 Structure-Based Drug Design

2012 ◽  
Vol 52 (5) ◽  
pp. 1079-1085 ◽  
Author(s):  
Puneet Kacker ◽  
Matteo Masetti ◽  
Martina Mangold ◽  
Giovanni Bottegoni ◽  
Andrea Cavalli
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Structure Based Drug Design ◽  
Bace 1

scholarly journals Molecular Dynamics Simulations of the Interaction of Mouse andTorpedoAcetylcholinesterase with Covalent Inhibitors Explain Their Differential Reactivity: Implications for Drug Design

2019 ◽  
Author(s):  
Nellore Bhanu Chandar ◽  
Irena Efremenko ◽  
Israel Silman ◽  
Jan M.L. Martin ◽  
Joel L. Sussman
Keyword(s):  
Molecular Dynamics ◽  
Drug Design ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Three Dimensional ◽  
Docking Studies ◽  
Covalent Modification ◽  
Phenylmethylsulfonyl Fluoride ◽  
Living Organisms ◽  
Dynamics Simulations

AbstractAlthough the three-dimensional structures of mouse andTorpedo californicaacetylcholinesterase are very similar, their responses to the covalent sulfonylating agents benzenesulfonyl fluoride and phenylmethylsulfonyl fluoride are qualitatively different. Both agents inhibit the mouse enzyme effectively by covalent modification of its active-site serine. In contrast, whereas theTorpedoenzyme is effectively inhibited by benzenesulfonyl fluoride, it is completely resistant to phenylmethylsulfonyl fluoride. A bottleneck midway down the active-site gorge in both enzymes restricts access of ligands to the active site at the bottom of the gorge. Molecular dynamics simulations revealed that the mouse enzyme is substantially more flexible than theTorpedoenzyme, suggesting that enhanced ‘breathing motions’ of the mouse enzyme relative to theTorpedoenzyme might explain why phenylmethylsulfonyl fluoride can reach the active site in mouse acetylcholinesterase, but not in theTorpedoenzyme. Accordingly, we performed docking of the two sulfonylating agents to the two enzymes, followed by molecular dynamics simulations. Whereas benzenesulfonyl fluoride closely approached the active-site serine in both mouse andTorpedoacetylcholinesterase in such simulations, phenylmethylsulfonyl fluoride was able to approach the active-site serine of mouse acetylcholinesterase - but remained trapped above the bottleneck in the case of theTorpedoenzyme. Our studies demonstrate that reliance on docking tools in drug design can produce misleading information. Docking studies should, therefore, also be complemented by molecular dynamics simulations in selection of lead compounds.Author summaryEnzymes are protein molecules that catalyze chemical reactions in living organisms, and are essential for their physiological functions. Proteins have well defined three-dimensional structures, but display flexibility; it is believed that this flexibility, known as their dynamics, plays a role in their function. Here we studied the neuronal enzyme acetylcholinesterase, which breaks down the neurotransmitter, acetylcholine. The active site of this enzyme is deeply buried, and accessed by a narrow gorge. A particular inhibitor, phenylmethylsulfonyl fluoride, is known to inhibit mouse acetylcholinesterase, but not that of the electric fish,Torpedo, even though their structures are very similar. A theoretical technique called molecular dynamics (MD) shows that the mouse enzyme is more flexible than theTorpedo enzyme. Furthermore, when the movement of the inhibitor down the gorge towards the active site is simulated using MD, the phenylmethylsulfonyl fluoride can reach the active site in the mouse enzyme, but not in theTorpedoenzyme, in which it remains trapped midway down the gorge. Our study emphasizes the importance of taking into account not only structure, but also dynamics, in designing drugs targeted towards proteins.

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