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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...

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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Fragment-based de novo ligand design by multiobjective evolutionary optimization.

Fabian Dey1, Amedeo Caflisch

  • 1Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Journal of Chemical Information and Modeling
|March 1, 2008
PubMed
Summary
This summary is machine-generated.

GANDI, a computational tool, designs novel drug inhibitors by assembling molecular fragments. It optimizes binding energy and similarity to known drugs, yielding synthetically accessible compounds for targets like CDK2.

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Area of Science:

  • Computational chemistry
  • Drug discovery
  • Molecular modeling

Background:

  • Fragment-based drug design (FBDD) is a key strategy in modern drug discovery.
  • Developing computational tools to automate and optimize de novo molecular design is crucial for efficient lead identification.
  • Understanding protein-ligand interactions, such as those in kinase binding sites, informs rational drug design.

Purpose of the Study:

  • To introduce GANDI (Genetic Algorithm-based de Novo Design of Inhibitors), a novel computational tool for automated fragment-based molecular design.
  • To evaluate GANDI's performance in designing inhibitors for a specific protein target, cyclin-dependent kinase 2 (CDK2).
  • To demonstrate GANDI's capability in optimizing molecular properties for drug-likeness and synthetic accessibility.

Main Methods:

  • GANDI employs a hybrid approach combining a genetic algorithm and tabu search to assemble molecular fragments.
  • The tool simultaneously optimizes force field energy and similarity metrics (2D or 3D) to known inhibitors or binding modes.
  • Scaffold hopping is facilitated by adjusting the weights of optimization terms, allowing exploration of diverse chemical spaces.

Main Results:

  • GANDI successfully designed molecules for CDK2 that form key hydrogen bonds with the hinge region, a characteristic of potent kinase inhibitors.
  • A top-ranked designed molecule exhibited a favorable predicted binding affinity and shared a key chemical moiety with a known nanomolar CDK2 inhibitor.
  • A significant portion of GANDI-designed molecules were found to be synthetically accessible, with several sharing scaffolds with commercially available compounds.

Conclusions:

  • GANDI is an effective computational tool for the de novo design of novel molecular inhibitors.
  • The simultaneous optimization of energy and similarity metrics, coupled with scaffold hopping capabilities, enhances the design process.
  • GANDI-designed molecules show promise for drug discovery due to their favorable predicted properties and synthetic accessibility.