scholarly journals Advances toward structure-based drug discovery for inflammasome targets

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Li Wang ◽  
Michael A. Crackower ◽  
Hao Wu
Keyword(s):  
Drug Discovery ◽  
High Resolution ◽  
Drug Design ◽  
Structural Biology ◽  
Drug Targets ◽  
Unmet Need ◽  
Structure Based Drug Design ◽  
Important Family ◽  
Recent Advances

Inflammasome proteins play an important role in many diseases of high unmet need, making them attractive drug targets. However, drug discovery for inflammasome proteins has been challenging in part due to the difficulty in solving high-resolution structures using cryo-EM or crystallography. Recent advances in the structural biology of NLRP3 and NLRP1 have provided the first set of data that proves a promise for structure-based drug design for this important family of targets.

scholarly journals Structural Biology in Drug Discovery and Drug Metabolism: Loughborough, 24–25 February 2003

2003 ◽  
Vol 25 (3) ◽  
pp. 34-35
Author(s):  
Clare Sansom
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Drug Metabolism ◽  
Research And Development ◽  
Structural Biology ◽  
Metabolic Pathways ◽  
Structure Based Drug Design

Researchers from industry and academia mingled at AstraZeneca's impressive research and development facilities at Charnwood, near Loughborough, in February for a Biochemical Society Focused Meeting that was concerned with the place of metabolism and metabolic pathways in structure-based drug design.

scholarly journals The Growing Role of Electron Microscopy in Anti-parasitic Drug Discovery

2019 ◽  
Vol 25 (39) ◽  
pp. 5279-5290
Author(s):  
R.M. Johnson ◽  
S. Rawson ◽  
M.J. McPhillie ◽  
C.W.G. Fishwick ◽  
S.P. Muench
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
High Resolution ◽  
Drug Design ◽  
Structural Information ◽  
Protein Structures ◽  
Parasite Protein ◽  
Structure Based Drug Design ◽  
Dramatic Rise ◽  
Review Reports

Background: Parasite diseases are a huge burden on human health causing significant morbidity and mortality. However, parasite structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasite derived proteins and have often relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. Results: In this review, we discuss the challenges associated with the structural determination of parasite proteins including the difficulties in obtaining sufficient quantities of protein. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasite protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in anti-parasite drug discovery. Conclusions: This review reports the progress that has been made in obtaining sufficient quantities of proteins for structural studies and the role EM may play in future structure based drug design programs. The outlook for future structure based drug design programs against some of the most devastating parasite diseases looks promising.

scholarly journals An Updated Review of Computer-Aided Drug Design and Its Application to COVID-19

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Arun Bahadur Gurung ◽  
Mohammad Ajmal Ali ◽  
Joongku Lee ◽  
Mohammad Abul Farah ◽  
Khalid Mashay Al-Anazi
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Drug Targets ◽  
Pharmacophore Modeling ◽  
Review Article ◽  
Drug Candidate ◽  
Computational Techniques ◽  
Computer Aided Drug Design ◽  
Structure Based Drug Design ◽  
Computer Aided

The recent outbreak of the deadly coronavirus disease 19 (COVID-19) pandemic poses serious health concerns around the world. The lack of approved drugs or vaccines continues to be a challenge and further necessitates the discovery of new therapeutic molecules. Computer-aided drug design has helped to expedite the drug discovery and development process by minimizing the cost and time. In this review article, we highlight two important categories of computer-aided drug design (CADD), viz., the ligand-based as well as structured-based drug discovery. Various molecular modeling techniques involved in structure-based drug design are molecular docking and molecular dynamic simulation, whereas ligand-based drug design includes pharmacophore modeling, quantitative structure-activity relationship (QSARs), and artificial intelligence (AI). We have briefly discussed the significance of computer-aided drug design in the context of COVID-19 and how the researchers continue to rely on these computational techniques in the rapid identification of promising drug candidate molecules against various drug targets implicated in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The structural elucidation of pharmacological drug targets and the discovery of preclinical drug candidate molecules have accelerated both structure-based as well as ligand-based drug design. This review article will help the clinicians and researchers to exploit the immense potential of computer-aided drug design in designing and identification of drug molecules and thereby helping in the management of fatal disease.

scholarly journals Structure-based drug design: aiming for a perfect fit

2017 ◽  
Vol 61 (5) ◽  
pp. 431-437 ◽  
Author(s):  
Rob L.M. van Montfort ◽  
Paul Workman
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Structural Biology ◽  
Protein Structures ◽  
Three Dimensional ◽  
Integral Membrane Protein ◽  
Open Science ◽  
Dimensional Structure ◽  
Structure Based Drug Design ◽  
X Ray

Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this editorial we provide a brief overview of the powerful impact of structure-based drug design (SBDD), which has its roots in computational and structural biology, with major contributions from both academia and industry. We describe advances in the application of SBDD for integral membrane protein targets that have traditionally proved very challenging. We emphasize the major progress made in fragment-based approaches for which success has been exemplified by over 30 clinical drug candidates and importantly three FDA-approved drugs in oncology. We summarize the articles in this issue that provide an excellent snapshot of the current state of the field of SBDD and fragment-based drug design and which offer key insights into exciting new developments, such as the X-ray free-electron laser technology, cryo-electron microscopy, open science approaches and targeted protein degradation. We stress the value of SBDD in the design of high-quality chemical tools that are used to interrogate biology and disease pathology, and to inform target validation. We emphasize the need to maintain the scientific rigour that has been traditionally associated with structural biology and extend this to other methods used in drug discovery. This is particularly important because the quality and robustness of any form of contributory data determines its usefulness in accelerating drug design, and therefore ultimately in providing patient benefit.

scholarly journals Abstract P-25: High-Resolution Cryo-Electron Microscopy Structure of the Staphylococcus Aureus Ribosome Brings to Light New Possible Drug Targets

2021 ◽  
Vol 11 (Suppl_1) ◽  
pp. S22-S23
Author(s):  
Alexander Golubev ◽  
Bulat Fatkhullin ◽  
Iskander Khusainov ◽  
Shamil Validov ◽  
Marat Yusupov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protein Synthesis ◽  
Drug Discovery ◽  
Drug Design ◽  
Messenger Rna ◽  
Drug Targets ◽  
Structural Data ◽  
New Drugs ◽  
Fine Tuning ◽  
Structure Based Drug Design

Background: Antibiotic resistance is a growing worldwide problem. One of the major resistant bacterial pathogens is Staphylococcus aureus, which became a burden of healthcare systems around the world. To overcome the issue, more drug discovery studies are needed. One of the main antibiotic targets is a ribosome – the central hub of protein synthesis. Structural data of the ribosome and its features are a crucial milestone for the effective development of new drugs, especially using structure-based drug design approaches. Apart from many small structural features, ribosome possesses rRNA modifications that play a role in the fine-tuning of protein synthesis. Detailed species-specific structural data of the S. aureus ribosome is also a useful model for understanding the resistance mechanisms. This information could help with the design of new antibiotics and the upgrading of old ones. The data on S. aureus ribosomal RNA modifications and corresponding modification enzymes are very limited. Our aim was to improve the current models of the S. aureus ribosome by determining its structure with functional ligands at a much higher resolution - thereby creating a foundation for structure-based drug design experiments and research of new drug targets. Methods: The S. aureus ribosome complex consists of three components: ribosome, fMet-tRNAfMet, mRNA and 70S ribosome. The complex from purified components was formed in vitro and applied to cryo-EM grids. Data was collected at Titan Krios with Gatan K2 detector (IGBMC, France). The data was processed and modeled in Relion 2.1, Chimera, Coot, and Phenix. Results: We determined the cryo-EM reconstruction at 3.2 Å resolution of the S. aureus ribosome with P-site tRNA, messenger RNA. Based on the experimental map and existing bioinformatic data, we at the first time identified and assigned 10 modifications of S. aureus rRNA. We analyzed the positions of rRNA modifications and their possible functions. Conclusion: In this study, we describe our structure of S. aureus ribosome with functional ligands. The present model is the highest resolution and most precise that is available at the moment. We propose a set of methyltransferases as targets for future drug discovery studies. The proposed methyltransferases and corresponding modifications may play an important role in protein synthesis and its regulation.

scholarly journals Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead

2020 ◽  
Vol 10 (12) ◽  
pp. 4248 ◽  
Author(s):  
Eduardo M. Bruch ◽  
Stéphanie Petrella ◽  
Marco Bellinzoni
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Structural Biology ◽  
Antiviral Drug ◽  
Dna Gyrase ◽  
Antibacterial Drug ◽  
Computer Aided Drug Design ◽  
Structure Based Drug Design ◽  
Long Time ◽  
Structural Coverage

Structure-based and computer-aided drug design approaches are commonly considered to have been successful in the fields of cancer and antiviral drug discovery but not as much for antibacterial drug development. The search for novel anti-tuberculosis agents is indeed an emblematic example of this trend. Although huge efforts, by consortiums and groups worldwide, dramatically increased the structural coverage of the Mycobacterium tuberculosis proteome, the vast majority of candidate drugs included in clinical trials during the last decade were issued from phenotypic screenings on whole mycobacterial cells. We developed here three selected case studies, i.e., the serine/threonine (Ser/Thr) kinases—protein kinase (Pkn) B and PknG, considered as very promising targets for a long time, and the DNA gyrase of M. tuberculosis, a well-known, pharmacologically validated target. We illustrated some of the challenges that rational, target-based drug discovery programs in tuberculosis (TB) still have to face, and, finally, discussed the perspectives opened by the recent, methodological developments in structural biology and integrative techniques.

scholarly journals Engineering of Challenging G Protein-Coupled Receptors for Structure Determination and Biophysical Studies

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1465
Author(s):  
Yann Waltenspühl ◽  
Janosch Ehrenmann ◽  
Christoph Klenk ◽  
Andreas Plückthun
Keyword(s):  
High Resolution ◽  
Drug Design ◽  
G Protein ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
G Protein Coupled Receptors ◽  
Resonance Spectroscopy ◽  
Structure Based Drug Design ◽  
Biophysical Studies ◽  
G Protein Coupled

Membrane proteins such as G protein-coupled receptors (GPCRs) exert fundamental biological functions and are involved in a multitude of physiological responses, making these receptors ideal drug targets. Drug discovery programs targeting GPCRs have been greatly facilitated by the emergence of high-resolution structures and the resulting opportunities to identify new chemical entities through structure-based drug design. To enable the determination of high-resolution structures of GPCRs, most receptors have to be engineered to overcome intrinsic hurdles such as their poor stability and low expression levels. In recent years, multiple engineering approaches have been developed to specifically address the technical difficulties of working with GPCRs, which are now beginning to make more challenging receptors accessible to detailed studies. Importantly, successfully engineered GPCRs are not only valuable in X-ray crystallography, but further enable biophysical studies with nuclear magnetic resonance spectroscopy, surface plasmon resonance, native mass spectrometry, and fluorescence anisotropy measurements, all of which are important for the detailed mechanistic understanding, which is the prerequisite for successful drug design. Here, we summarize engineering strategies based on directed evolution to reduce workload and enable biophysical experiments of particularly challenging GPCRs.

Current Scenario in Structure and Ligand-Based Drug Design on Anti-colon Cancer Drugs

2019 ◽  
Vol 24 (32) ◽  
pp. 3829-3841 ◽  
Author(s):  
Lakshmanan Loganathan ◽  
Karthikeyan Muthusamy
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Anticancer Agent ◽  
Computational Power ◽  
Cancer Drugs ◽  
Recent Advances ◽  
Anti Cancer ◽  
Drug Designing ◽  
Current Scenario ◽  
Molecular Modeling Studies

Worldwide, colorectal cancer takes up the third position in commonly detected cancer and fourth in cancer mortality. Recent progress in molecular modeling studies has led to significant success in drug discovery using structure and ligand-based methods. This study highlights aspects of the anticancer drug design. The structure and ligand-based drug design are discussed to investigate the molecular and quantum mechanics in anti-cancer drugs. Recent advances in anticancer agent identification driven by structural and molecular insights are presented. As a result, the recent advances in the field and the current scenario in drug designing of cancer drugs are discussed. This review provides information on how cancer drugs were formulated and identified using computational power by the drug discovery society.

Experimental and Computational Approaches to Improve Binding Affinity in Chemical Biology and Drug Discovery

2020 ◽  
Vol 20 (19) ◽  
pp. 1651-1660
Author(s):  
Anuraj Nayarisseri
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Binding Affinity ◽  
Chemical Biology ◽  
De Novo ◽  
Structure Based Drug Design ◽  
Computational Approaches ◽  
Drug Designing ◽  
Traditional Drug ◽  
Computer Based

Drug discovery is one of the most complicated processes and establishment of a single drug may require multidisciplinary attempts to design efficient and commercially viable drugs. The main purpose of drug design is to identify a chemical compound or inhibitor that can bind to an active site of a specific cavity on a target protein. The traditional drug design methods involved various experimental based approaches including random screening of chemicals found in nature or can be synthesized directly in chemical laboratories. Except for the long cycle design and time, high cost is also the major issue of concern. Modernized computer-based algorithm including structure-based drug design has accelerated the drug design and discovery process adequately. Surprisingly from the past decade remarkable progress has been made concerned with all area of drug design and discovery. CADD (Computer Aided Drug Designing) based tools shorten the conventional cycle size and also generate chemically more stable and worthy compounds and hence reduce the drug discovery cost. This special edition of editorial comprises the combination of seven research and review articles set emphasis especially on the computational approaches along with the experimental approaches using a chemical synthesizing for the binding affinity in chemical biology and discovery as a salient used in de-novo drug designing. This set of articles exfoliates the role that systems biology and the evaluation of ligand affinity in drug design and discovery for the future.

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