Allostery and Missense Mutations as Intermittently Linked Promising Aspects of Modern Computational Drug Discovery DOI Creative Commons
Özlem Taştan Bishop, Thommas M. Musyoka, Victor Barozi

et al.

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 434(17), P. 167610 - 167610

Published: April 28, 2022

Drug research and development is a multidisciplinary field with its own successes. Yet, given the complexity of process, it also faces challenges over long stages even includes those that develop once drug marketed, i.e. toxicity resistance. Better success can be achieved via well designed criteria in early stages. Here, we introduce concepts allostery missense mutations, argue incorporation these two intermittently linked biological phenomena into computational discovery would help to reduce attrition risk later process. We discuss individual or concert mechanisms actions mutations allostery. Design allosteric drugs challenging compared orthosteric drugs, yet they have been gaining popularity recent years as alternative systems for therapeutic regulation proteins an action-at-a-distance mode non-invasive mechanisms. propose easy-to-apply protocol which considers mutation effect, detail three case studies focusing on (1) analysis effect related isoniazid resistance tuberculosis; (2) identification cryptic pocket presence falcipain-2 malarial target; (3) deciphering effects SARS-CoV-2 evolutionary potential modulator changes communication paths.

Language: Английский

Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development DOI Creative Commons
Zongyang Lv,

Kristin E. Cano,

Lijia Jia

et al.

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 9

Published: Feb. 3, 2022

The emergence of severe acute respiratory syndrome (SARS-CoV-2) in 2019 marked the third occurrence a highly pathogenic coronavirus human population since 2003. As death toll surpasses 5 million globally and economic losses continue, designing drugs that could curtail infection disease progression is critical. In US, three effective Food Drug Administration (FDA)–authorized vaccines are currently available, Remdesivir approved for treatment hospitalized patients. However, moderate vaccination rates sustained evolution new viral variants necessitate ongoing search antivirals. Several proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them papain-like protease (PLpro) main (Mpro). Inhibition these proteases would target replication, maturation, suppression host innate immune responses. Knowledge inhibitors assays viruses were quickly adopted research. Potential candidates identified to show inhibitory effects against PLpro Mpro, both biochemical replication cells. These results encourage further optimizations improve prophylactic therapeutic efficacy. this review, we examine latest developments potential small-molecule peptide how structural biology greatly facilitates process.

Language: Английский

Citations

77
Accelerating COVID-19 Research Using Molecular Dynamics Simulation DOI
Aditya K. Padhi, Soumya Lipsa Rath, Timir Tripathi

et al.

The Journal of Physical Chemistry B, Journal Year: 2021, Volume and Issue: 125(32), P. 9078 - 9091

Published: July 28, 2021

The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided opportunity make rational scientific breakthroughs in time crisis. Advancements these technologies recent years become an indispensable tool studying protein structure, function, dynamics, interactions, discovery. Integrating structural data obtained from high-resolution methods with MD helped comprehending process infection pathogenesis, well SARS-CoV-2 maturation host cells, short duration time. It also guided us identify prioritize targets new chemical entities, repurpose drugs. Here, we discuss how simulation been explored by community accelerate guide translational research on past year. We considered future directions researchers, where can help fill existing gaps research.

Language: Английский

Citations

67
TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity DOI Creative Commons
Wenchun Fan, Katrina B. Mar, Levent Sari

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(13), P. 3410 - 3425.e17

Published: May 31, 2021

Language: Английский

Citations

64
Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease DOI Open Access
János András Mótyán, Mohamed Mahdi, Gyula Hoffka

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3507 - 3507

Published: March 23, 2022

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of most devastating pandemics recent times. The lack potent novel antivirals had led to global health crises; however, emergence and approval inhibitors viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in therapeutic front but also context prophylaxis against infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, lessons learnt from previous currently ongoing taught us that these can easily escape selection pressure through vital target amino acid residues monotherapeutic settings. In this paper, we review nirmatrelvir its binding SARS-CoV-2 Mpro draw a comparison HIV were rendered obsolete resistance mutations, emphasizing potential pitfalls design may be important relevance long-term use SARS-CoV-2.

Language: Английский

Citations

63
Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2 DOI Creative Commons
Kaifu Gao, Rui Wang, Jiahui Chen

et al.

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(13), P. 11287 - 11368

Published: May 20, 2022

Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component combating disease 2019 (COVID-19) due to their low cost, efficiency, fact that they are free from safety ethical constraints. Additionally, mechanism governs global transmission SARS-CoV-2 cannot be revealed individual experiments was discovered by integrating genotyping massive viral sequences, biophysical modeling protein-protein deep mutational data, learning, advanced mathematics. There exists a tsunami literature on molecular modeling, simulations, predictions related developments drugs, vaccines, antibodies, diagnostics. To provide readers with quick update about this literature, we present comprehensive systematic methodology-centered review. Aspects such as biophysics, bioinformatics, cheminformatics, machine mathematics discussed. review will beneficial researchers who looking ways contribute those interested status field.

Language: Английский

Citations

58
Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach DOI Creative Commons
Taj Mohammad,

Arunabh Choudhury,

Insan Habib

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2021, Volume and Issue: 11

Published: Oct. 13, 2021

A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising and becomes more lethal for humankind than ever. Mutations structural proteins of SARS-CoV-2, i.e., spike surface glycoprotein (S), envelope (E), membrane (M) nucleocapsid (N), replication machinery enzymes, protease (M pro ) RNA-dependent RNA polymerase (RdRp) creating complexities towards pathogenesis available COVID-19 therapeutic strategies. This study analyzes how minimal variation these especially S protein at genomic/proteomic level, affects pathogenesis. variations are discussed light failure small molecule development We have performed in-depth sequence- structure-based analyses to get deeper insights into mechanism pathogenesis, structure-function relationships, modern approaches. Structural functional consequences selected mutations on their association virulency human health detail our comparative genomics analysis.

Language: Английский

Citations

58
Lead Discovery of SARS-CoV-2 Main Protease Inhibitors through Covalent Docking-Based Virtual Screening DOI Open Access
Giorgio Amendola, Roberta Ettari, Santo Previti

et al.

Journal of Chemical Information and Modeling, Journal Year: 2021, Volume and Issue: 61(4), P. 2062 - 2073

Published: March 30, 2021

During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for worldwide health and economy, propelling unprecedented efforts to discover drugs its prevention cure. At end of year, these have culminated with approval vaccines by American Food Drug Administration (FDA) European Medicines Agency (EMA) giving new hope future. On other hand, clinical data underscore urgent need effective treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against severe acute respiratory syndrome 2 (SARS-CoV-2) Mpro chymotrypsin-like cysteine protease employing our in-house database peptide non-peptide ligands characterized different types warheads acting as Michael acceptors. To end, employed AutoDock4 docking software customized predict formation covalent adduct target protein. vitro verification inhibition properties most promising candidates allowed us identify two lead inhibitors that will deserve further optimization. From computational point view, work demonstrates predictive power suggests application in silico large chemical libraries potential binders SARS-CoV-2 enzyme.

Language: Английский

Citations

48
Molecular docking and dynamics study to explore phytochemical ligand molecules against the main protease of SARS-CoV-2 from extensive phytochemical datasets DOI
Shafi Mahmud, Mohasana Akter Mita, Suvro Biswas

et al.

Expert Review of Clinical Pharmacology, Journal Year: 2021, Volume and Issue: 14(10), P. 1305 - 1315

Published: July 24, 2021

The high transmission and pathogenicity of SARS-CoV-2 has led to a pandemic that halted the world's economy health. newly evolved strains scarcity vaccines worsened situation. main protease (Mpro) can act as potential target due its role in viral replication conservation level.In this study, we have enlisted more than 1100 phytochemicals from Asian plants based on deep literature mining. compounds library was screened against Mpro SARS-CoV-2.The selected three ligands, Flemichin, Delta-Oleanolic acid, Emodin 1-O-beta-D-glucoside had binding energy -8.9, -8.7 KJ/mol respectively. bind active groove at; Cys145, Glu166, His41, Met49, Pro168, Met165, Gln189. multiple descriptors simulation study; root mean square deviation, fluctuation, radius gyration, hydrogen bond, solvent accessible surface area confirms stable nature protein-ligand complexes. Furthermore, post-md analysis rigidness docked poses over trajectories.Our combinatorial drug design approaches may help researchers identify suitable candidates SARS-CoV-2.

Language: Английский

Citations

46
Ligand-based design, synthesis, computational insights, andin vitrostudies of novelN-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease DOI Creative Commons
Mohamed Elagawany, Ayman Abo Elmaaty,

Ahmed Mostafa

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 2112 - 2132

Published: July 31, 2022

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development new effective therapeutic interventions for battle against SARS-CoV-2. A series

Language: Английский

Citations

35
MD simulations indicate Omicron P132H of SARS-CoV-2 Mpro is a potential allosteric mutant involved in modulating the dynamics of catalytic site entry loop DOI
Zahoor Ahmad Bhat,

Mohd Muzammil Khan,

Ayyub Rehman

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 262, P. 130077 - 130077

Published: Feb. 10, 2024

Language: Английский

Citations

7