Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

2022 ◽  
Author(s):  
Anoop Narayanan ◽  
Shay A. Toner ◽  
Joyce Jose
Keyword(s):  
Drug Design ◽  
Protease Inhibitors ◽  
Drug Repurposing ◽  
Inhibitor Design ◽  
Rational Structure ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Clinical Drugs

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

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.

ChemInform Abstract: Structure-Based Drug Design of Nonpeptidic P2 Substituents for HIV-1 Protease Inhibitors.

ChemInform ◽  
2010 ◽  
Vol 26 (34) ◽  
pp. no-no
Author(s):  
V. J. KALISH ◽  
J. H. TATLOCK ◽  
J. F. II DAVIES ◽  
S. W. KALDOR ◽  
B. A. DRESSMAN ◽  
...  
Keyword(s):  
Drug Design ◽  
Protease Inhibitors ◽  
Structure Based Drug Design ◽  
Abstract Structure ◽  
Hiv 1

scholarly journals An Overview of Computational Approaches in Structure Based Drug Design

1970 ◽  
Vol 2 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Dipali Singh ◽  
Anushree Tripathi ◽  
Gautam Kumar
Keyword(s):  
Drug Design ◽  
Computer Aided Drug Design ◽  
Structure Based Drug Design ◽  
Computational Approaches ◽  
Ras Protein ◽  
Design Structure ◽  
Drug Lead ◽  
Computer Aided ◽  
Drug Designing

Drug design is a costly and difficult process. Drug must fulfill several criteria of being active, nontoxic and bioavailable. The conventional way of synthesizing drugs is a monotonous process. But computer aided drug design is a proficient way to overcome the tedious process of conventional method. Drugs can be designed computationally by structure or target based drug designing (SBDD). This review summarizes the methods of structure based drug design, usage of related softwares and a case study that explores to find a suitable drug (lead) molecule for the mutated state of H-Ras protein in order to prevent complex formation with Raf protein.Keywords: computer aided drug design; structure based drug design; Ras-proteinDOI: http://dx.doi.org/10.3126/njb.v2i1.5680Nepal Journal of Biotechnology Jan.2012, Vol.2(1): 53-61

Combined approach of homology modeling, molecular dynamics, and docking: computer-aided drug discovery

2019 ◽  
Vol 4 (10) ◽  
Author(s):  
Varun Chahal ◽  
Sonam Nirwan ◽  
Rita Kakkar
Keyword(s):  
Drug Design ◽  
Homology Modeling ◽  
3D Structure ◽  
Structure Based Drug Design ◽  
Combined Application ◽  
Cytoplasmic Proteins ◽  
Software Algorithms ◽  
Computer Aided ◽  
Drug Designing ◽  
Process Structure

Abstract With the continuous development in software, algorithms, and increase in computer speed, the field of computer-aided drug design has been witnessing reduction in the time and cost of the drug designing process. Structure based drug design (SBDD), which is based on the 3D structure of the enzyme, is helping in proposing novel inhibitors. Although a number of crystal structures are available in various repositories, there are various proteins whose experimental crystallization is difficult. In such cases, homology modeling, along with the combined application of MD and docking, helps in establishing a reliable 3D structure that can be used for SBDD. In this review, we have reported recent works, which have employed these three techniques for generating structures and further proposing novel inhibitors, for cytoplasmic proteins, membrane proteins, and metal containing proteins. Also, we have discussed these techniques in brief in terms of the theory involved and the various software employed. Hence, this review can give a brief idea about using these tools specifically for a particular problem.

scholarly journals Computer Aided Drug Designing

2017 ◽  
Vol 6 (1) ◽  
pp. 1433
Author(s):  
Vijay Kumar Sehgal ◽  
Supratik Das ◽  
Anand Vardhan
Keyword(s):  
Drug Design ◽  
Medical Science ◽  
Quantitative Structure ◽  
Structure Property ◽  
Structure Based Drug Design ◽  
Safety Issues ◽  
Computer Aided ◽  
Drug Designing ◽  
Quantitative Structure Property Relationships

Designing of drugs and their development are a time and resource consuming process. There is an increasing effort to introduce the role of computational approach to chemical and biological space in order to organise the design and development of drugs and their optimisation. The role of Computer Aided Drug Designing (CADD) are nowadays expressed in Nanotechnology, Molecular biology, Biochemistry etc. It is a diverse discipline where various forms of applied and basic researches are interlinked with each other. Computer aided or in Silico drug designing is required to detect hits and leads. Optimise/ alter the absorption, distribution, metabolism, excretion and toxicity profile and prevent safety issues. Some commonly used computational approaches include ligand-based drug design, structure-based drug design, and quantitative structure-activity and quantitative structure-property relationships. In today's world, due to an avid interest of regulatory agencies and, even pharmaceutical companies in advancing drug discovery and development process by computational means, it is expected that its power will grow as technology continues to evolve. The main purpose of this review article is to give a brief glimpse about the role Computer Aided Drug Design has played in modern medical science and the scope it carries in the near future, in the service of designing newer drugs along with lesser expenditure of time and money.

scholarly journals Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Isabella A. Guedes ◽  
Leon S. C. Costa ◽  
Karina B. dos Santos ◽  
Ana L. M. Karl ◽  
Gregório K. Rocha ◽  
...  
Keyword(s):  
Drug Design ◽  
Therapeutic Targets ◽  
Web Server ◽  
Drug Repurposing ◽  
World Health ◽  
Design Strategies ◽  
Structure Based Drug Design ◽  
N Protein ◽  
The Impact ◽  
The Web

AbstractThe COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br.

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