Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead

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.

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COMPUTER AIDED DRUG DESIGN: AN OVERVIEW

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v8i5.1894 ◽

2018 ◽

Vol 8 (5) ◽

pp. 504-509 ◽

Cited By ~ 12

Author(s):

Surabhi Surabhi ◽

BK Singh

Keyword(s):

Molecular Docking ◽

Drug Discovery ◽

Virtual Screening ◽

Drug Design ◽

Computer Aided Drug Design ◽

Structure Based Drug Design ◽

Drug Discovery And Development ◽

Research Areas ◽

Computer Aided ◽

Pharmaceutical Industries

Discovery and development of a new drug is generally known as a very complex process which takes a lot of time and resources. So now a day’s computer aided drug design approaches are used very widely to increase the efficiency of the drug discovery and development course. Various approaches of CADD are evaluated as promising techniques according to their need, in between all these structure-based drug design and ligand-based drug design approaches are known as very efficient and powerful techniques in drug discovery and development. These both methods can be applied with molecular docking to virtual screening for lead identification and optimization. In the recent times computational tools are widely used in pharmaceutical industries and research areas to improve effectiveness and efficacy of drug discovery and development pipeline. In this article we give an overview of computational approaches, which is inventive process of finding novel leads and aid in the process of drug discovery and development research. Keywords: computer aided drug discovery, structure-based drug design, ligand-based drug design, virtual screening and molecular docking

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Advances toward structure-based drug discovery for inflammasome targets

Journal of Experimental Medicine ◽

10.1084/jem.20211147 ◽

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.

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

The Biochemist ◽

10.1042/bio02503034 ◽

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.

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

BioMed Research International ◽

10.1155/2021/8853056 ◽

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.

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Structure-based drug design: aiming for a perfect fit

Essays in Biochemistry ◽

10.1042/ebc20170052 ◽

2017 ◽

Vol 61 (5) ◽

pp. 431-437 ◽

Cited By ~ 31

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.

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An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

Methods in Molecular Biology - G Protein-Coupled Receptors in Drug Discovery ◽

10.1007/978-1-60327-317-6_4 ◽

2009 ◽

pp. 51-66 ◽

Cited By ~ 80

Author(s):

Kenneth Lundstrom

Keyword(s):

Drug Discovery ◽

Drug Design ◽

Structural Biology ◽

Structure Based Drug Design

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

Current Topics in Medicinal Chemistry ◽

10.2174/156802662019200701164759 ◽

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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Re-Designing Hazardous Chemicals with Target-Specific Toxicities by Learning from Structure-Based Drug Design

10.26434/chemrxiv.7001054 ◽

2018 ◽

Author(s):

Traci Clymer ◽

Vanessa Vargas ◽

Eric Corcoran ◽

Robin Kleinberg ◽

Jakub Kostal

Keyword(s):

Drug Discovery ◽

Drug Design ◽

Adverse Effects ◽

Environmental Health ◽

In Silico ◽

Adverse Outcomes ◽

Design Stage ◽

Hazardous Chemicals ◽

Structure Based Drug Design ◽

Computational Drug Discovery

Chemicals are the basis of our society and economy, yet many existing chemicals are known to have unintended adverse effects on human and environmental health. Testing all existing and new chemicals on animals is both economically and ethically unfeasible. In this paper, a new in silico framework is presented that affords redesign of existing hazardous chemicals in commerce based on specific molecular initiating events in their adverse outcomes pathways. Our approach is based on a successful methodology implemented in computational drug discovery, and promises to dramatically lower costs associated with new chemical development by synergistically addressing chemical function and safety at the design stage. <br>

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