Acylating Agents as Enzyme Inhibitors and Understanding Their Reactivity for Drug Design

2002 ◽  
Vol 45 (13) ◽  
pp. 2850-2856 ◽  
Author(s):  
Nicholas O. Sykes ◽  
Simon J. F. Macdonald ◽  
Michael I. Page
Keyword(s):  
Drug Design ◽  
Enzyme Inhibitors

scholarly journals A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI

2020 ◽  
Vol 13 (11) ◽  
pp. 338
Author(s):  
Joanna Bojarska ◽  
Milan Remko ◽  
Martin Breza ◽  
Izabela Madura ◽  
Andrzej Fruziński ◽  
...  
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Rational Design ◽  
Enzyme Inhibitors ◽  
Building Blocks ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Supramolecular Synthons ◽  
Comprehensive Classification ◽  
Proline Derivatives

Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO−), -N+ and -COOH(-COO−), -NH and -COOH(-COO−), -NH+ and -COOH(-COO−), and -NH2+ and -COOH(-COO−). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies.

Molecular Docking Studies and Inhibition Properties of Some Antineoplastic Agents against Paraoxonase-I

2020 ◽  
Vol 20 (7) ◽  
pp. 887-896 ◽  
Author(s):  
Yeliz Demir ◽  
Cüneyt Türkeş ◽  
Şükrü Beydemir
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Antineoplastic Agents ◽  
Enzyme Inhibitors ◽  
Competitive Inhibition ◽  
Specific Activity ◽  
Docking Studies ◽  
Irinotecan Hydrochloride ◽  
Ic50 Values ◽  
Pemetrexed Disodium

Background: Currently, most of the drugs used in clinical applications show their pharmacological influences by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug design for many diseases. Objective: The current study aimed to contribute to this growing drug design field (i.e., medicine discovery and development) by analyzing enzyme-drug interactions. Methods: For this reason, Paraoxonase-I (PON1) enzyme was purified from fresh human serum by using rapid chromatographic techniques. Additionally, the inhibition effects of some antineoplastic agents were researched on the PON1. Results: The enzyme was obtained with a specific activity of 2603.57 EU/mg protein. IC50 values for pemetrexed disodium, irinotecan hydrochloride, dacarbazine, and azacitidine were determined to be 9.63μM, 30.13μM, 53.31μM, and 21.00mM, respectively. These agents found to strongly inhibit PON1, with Ki constants ranging from 8.29±1.47μM to 23.34±2.71mM. Dacarbazine and azacitidine showed non-competitive inhibition, while other drugs showed competitive inhibition. Furthermore, molecular docking was performed using maestro for these agents. Among these, irinotecan hydrochloride and pemetrexed disodium possess the binding energy of -5.46 and -8.43 kcal/mol, respectively. Conclusion: The interaction studies indicated that these agents with the PON1 possess binding affinity.

Case studies in automatic modelling of thrombin, alpha-lactalbumin and other proteins, and implications for drug design

1992 ◽  
Vol 99 (1-2) ◽  
pp. 123-136 ◽  
Author(s):  
E. Platt ◽  
B. Robson
Keyword(s):  
Drug Design ◽  
Enzyme Inhibitors ◽  
Dynamic Nature ◽  
Crystallographic Groups ◽  
X Ray ◽  
X Ray Crystallography ◽  
Starting Point ◽  
Long Timescales ◽  
Surface Loops

Synopsis:In order to investigate and demonstrate objective modelling of proteins as a basis for drug design, we have sought to model several proteins in particularly persuasive circumstances. This is either (a) by filing the results of the model with an independent institution prior to X-ray determination of their structure, or (b) by using wholly automatic, general and reproducible methods, or (c) most often by both. Results suggest the ability to predict the core of the protein to an accuracy of about 1 Å rms deviation between predicted and experimental all-atom coordinates, and of surface loops in the range 1-4 Å rms deviation. Although the upper end of the latter scale seems disturbing, it turns out that many of the surface loops show such large variations for the same protein as studied by different crystallographic groups, particularly when no common protein is used as a starting point for refinement in both cases. Recognising the dynamic nature of some loops on enzymes, and including in the calculation the ability to handle dynamics over long timescales, allows analysis and refinement of enzyme inhibitors as pharmaceuticals. Here we analyse these aspects, particularly by reference to X-ray crystallography data.

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