Role of structural biology methods in drug discovery

Nasim, Fouzia; Qureshi, Insaf Ahmed

doi:10.1016/b978-0-323-90264-9.00022-2

Cited by 4 publications

(5 citation statements)

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“…Crystallography and other structural techniques, such as nuclear magnetic resonance or cryo-electron microscopy, have contributed significantly to structure-based drug discovery (Nasim & Qureshi, 2022). Insight into protein structure, especially of protein-lead compound complexes, could provide crucial information for successfully improving the designed compound, both in its increased affinity toward the disease target protein and its decreased affinity for all remaining proteins to avoid possible toxic side effects.…”

Section: Discussionmentioning

confidence: 99%

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From X-ray crystallographic structure to intrinsic thermodynamics of protein–ligand binding using carbonic anhydrase isozymes as a model system

Paketurytė-Latvė,

Smirnov,

Manakova

et al. 2024

IUCrJ

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Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein–ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure–thermodynamics correlations for the novel inhibitors of CA IX is discussed – an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein–Ligand Binding Database to understand general protein–ligand recognition principles that could be used in drug discovery.

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Section: Discussionmentioning

confidence: 99%

“…Structural biology plays a central role in drug discovery (Renaud et al, 2016;Nasim & Qureshi, 2022). Small-molecular-weight organic compounds could be biologically active due to binding to proteins and other macromolecules.…”

Section: Introductionmentioning

confidence: 99%

From X-ray crystallographic structure to intrinsic thermodynamics of protein–ligand binding using carbonic anhydrase isozymes as a model system

Paketurytė-Latvė,

Smirnov,

Manakova

et al. 2024

IUCrJ

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“…The use of structural biology in drug discovery has made it possible for researchers to design inhibitors with enriched specificities toward their corresponding targets. 98 These macromolecular structures can be retrieved from PDB which is a database comprising of information related to atomic coordinates of proteins that are determined by scientists across the globe. PDB is used on a regular basis for the derivation of inhibitors after retrieving atomic coordinates of target proteins, and some of the aaRSs structures from parasites other than trypanosomatids have been used to set a framework for designing drugs.…”

Section: Role Of Structural Biology In Designing Inhibitors Against T...mentioning

confidence: 99%

“…The use of structural biology in drug discovery has made it possible for researchers to design inhibitors with enriched specificities toward their corresponding targets . These macromolecular structures can be retrieved from PDB which is a database comprising of information related to atomic coordinates of proteins that are determined by scientists across the globe.…”

Section: Role Of Structural Biology In Designing Inhibitors Against T...mentioning

confidence: 99%

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Nasim

Qureshi

2023

ACS Omega

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The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.

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“…Nasim and Qureshi in their chapter about the "Role of structural biology methods in drug discovery" provide a good schematic illustration of the methods involved in drug discovery and development in the field of PM [5].…”

Section: Introductionmentioning

confidence: 99%

Peptides and peptidоmimetics in neuropharmacology (Review)

N. Encheva-Stoykova,

S. Tsekova,

Staykov

et al. 2023

JCTM

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Peptides and peptidomimetics are a major field of bioorganic chemistry research. We endeavored to describe the current trends in medicinal and bioorganic chemistry regarding the design of drug molecules which are peptide mimetics. To this end, we reviewed the literature regarding peptidomimetics classification, new research data on innovative potential drug molecules, current research, and its perspectives. Potential or current neuropharmacological agents that possess a peptide bond in their molecules and can be used in the treatment of pain or Alzheimer's disease are of particular interest to our study. The inclusion criteria required that the studies explore peptides, peptide mimetics, and peptidomimetics or mimetics of peptides that show biological activity in the central/peripheral nervous system. Electronic search strategies were developed and undertaken, and relevant articles were selected and reviewed. A considerable number of pharmacological agents showing pharmacotherapeutic relevance were identified and reviewed regarding biological activity in the nervous system. The ones more closely reviewed are prospective or proven effective neuropharmacological agents that are analogs of peptides/oligopeptides. The potential for discovery of various peptides and peptidomimetics, which can affect the pathogenesis of pain, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and others) offers to broaden the scientific horizon; in the end leading to the synthesis of potential alternatives to current pharmacotherapeutics. Translational research can be encouraged after careful consideration of the risk-benefit ratio.

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Role of structural biology methods in drug discovery

Cited by 4 publications

References 74 publications

From X-ray crystallographic structure to intrinsic thermodynamics of protein–ligand binding using carbonic anhydrase isozymes as a model system

From X-ray crystallographic structure to intrinsic thermodynamics of protein–ligand binding using carbonic anhydrase isozymes as a model system

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Peptides and peptidоmimetics in neuropharmacology (Review)

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