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 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.

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.

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 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.

The structure of chitinases and prospects for structure-based drug design

1995 ◽  
Vol 73 (S1) ◽  
pp. 1142-1146 ◽  
Author(s):  
Jon D. Robertus ◽  
P. John Hart ◽  
Arthur F. Monzingo ◽  
Edward Marcotte ◽  
Thomas Hollis
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Mechanism Of Action ◽  
Active Site ◽  
Antifungal Agents ◽  
Structure Based Drug Design ◽  
X Ray ◽  
Class Ii Chitinase ◽  
Transition State Geometry ◽  
Chitinase Inhibitors

Many fungi, including pathogenic strains, require proper chitin metabolism to assure normal cell wall replication. Chitinase hydrolyzes chitin; inhibition of endogenous chitinases or application of extracellular chitinases can disrupt fungal division. It is possible that chitinase inhibitors could be used as antifungal agents. We have solved the X-ray structure of a class II chitinase from barley and proposed a mechanism of action. The enzyme has a structural core similar to lysozyme and probably acts in a similar catalytic manner. The enzyme structure can, in principle, be used to identify small molecules that will bind avidly to the active site and act as inhibitors. Those inhibitors that embody transition state geometry are likely to be particularly effective. Key words: chitinase, mechanism of action, drug design.

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