Computational approaches streamlining drug discovery

Nature, Journal Year: 2023, Volume and Issue: 616(7958), P. 673 - 685

Published: April 26, 2023

Computer-aided drug discovery has been around for decades, although the past few years have seen a tectonic shift towards embracing computational technologies in both academia and pharma. This is largely defined by flood of data on ligand properties binding to therapeutic targets their 3D structures, abundant computing capacities advent on-demand virtual libraries drug-like small molecules billions. Taking full advantage these resources requires fast methods effective screening. includes structure-based screening gigascale chemical spaces, further facilitated iterative approaches. Highly synergistic are developments deep learning predictions target activities lieu receptor structure. Here we review recent advances technologies, potential reshaping whole process development, as well challenges they encounter. We also discuss how rapid identification highly diverse, potent, target-selective ligands protein can democratize process, presenting new opportunities cost-effective development safer more small-molecule treatments. Recent approaches application streamlining discussed.

Language: Английский

---

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 14, 2022

The main proteases (M

Language: Английский

---

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Science Advances, Journal Year: 2023, Volume and Issue: 9(13)

Published: March 31, 2023

Vaccines and drugs have helped reduce disease severity blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, increasing selective pressures potential to yield viral variants capable resisting these interventions. Here, we investigate susceptibility natural main protease [Mpro; 3C-like (3CLpro)] SARS-CoV-2 inhibitors. Multiple single amino acid changes in Mpro confer resistance nirmatrelvir (the active component Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different mutation profile. Importantly, phylogenetic analyses indicate that several resistant pre-existed introduction into human population are spreading. These results encourage monitoring development inhibitors other antiviral with mechanisms action profiles for combinatorial therapy.

Language: Английский

---

Accelerating antiviral drug discovery: lessons from COVID-19

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(7), P. 585 - 603

Published: May 12, 2023

Language: Английский

---

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(18), P. 12651 - 12677

Published: Sept. 6, 2023

Target-based drug discovery is the dominant paradigm of discovery; however, a comprehensive evaluation its real-world efficiency lacking. Here, manual systematic review about 32000 articles and patents dating back to 150 years ago demonstrates apparent inefficiency. Analyzing origins all approved drugs reveals that, despite several decades dominance, only 9.4% small-molecule have been discovered through "target-based" assays. Moreover, therapeutic effects even this minimal share cannot be solely attributed reduced their purported targets, as they depend on numerous off-target mechanisms unconsciously incorporated by phenotypic observations. The data suggest that reductionist target-based may cause productivity crisis in discovery. An evidence-based approach enhance seems prioritizing, selecting optimizing molecules, higher-level observations are closer sought-after using tools like artificial intelligence machine learning.

Language: Английский

---

Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115503 - 115503

Published: May 18, 2023

Language: Английский

---

Past, Present, and Future Perspectives on Computer-Aided Drug Design Methodologies

Molecules, Journal Year: 2023, Volume and Issue: 28(9), P. 3906 - 3906

Published: May 5, 2023

The application of computational approaches in drug discovery has been consolidated the last decades. These families techniques are usually grouped under common name "computer-aided design" (CADD), and they now constitute one pillars pharmaceutical pipelines many academic industrial environments. Their implementation demonstrated to tremendously improve speed early steps, allowing for proficient rational choice proper compounds a desired therapeutic need among extreme vastness drug-like chemical space. Moreover, CADD allows rationalization biochemical interactive processes interest at molecular level. Because this, tools extensively used also field 3D design optimization entities starting from structural information targets, which can be experimentally resolved or obtained with other computer-based techniques. In this work, we revised state-of-the-art computer-aided methods, focusing on their different scenarios biological interest, not only highlighting great potential benefits, but discussing actual limitations eventual weaknesses. This work considered brief overview methods discovery.

Language: Английский

---

Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115772 - 115772

Published: Aug. 28, 2023

Language: Английский

---

Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir “S-217622”: A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species

ACS Omega, Journal Year: 2023, Volume and Issue: 8(6), P. 5234 - 5246

Published: Jan. 30, 2023

Lately, nitrogenous heterocyclic antivirals, such as nucleoside-like compounds, oxadiazoles, thiadiazoles, triazoles, quinolines, and isoquinolines, topped the therapeutic scene promising agents of choice for treatment severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections their accompanying ailment, disease 2019 (COVID-19). At same time, continuous emergence new strains SARS-CoV-2, like Omicron variant its multiple sublineages, resulted in a defiance enduring COVID-19 battle. Ensitrelvir (S-217622) is newly discovered orally active noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities, exhibiting nanomolar potencies against different SARS-CoV-2 variants. S-217622 effectively nonspecifically hits main protease (Mpro) enzyme broad scope coronaviruses. Herein, present computational/biological study, we tried to extend these previous findings prove universal activities this investigational any coronavirus, irrespective type, through synchronously acting on most unchanged replication enzymes/proteins, including (in addition Mpro), e.g., highly conserved RNA-dependent RNA polymerase (RdRp) 3'-to-5' exoribonuclease (ExoN). Biochemical evaluation proved, using vitro anti-RdRp/ExoN bioassay, that can potently inhibit coronaviruses, virulent extremely minute anti-RdRp half-maximal effective concentration (EC50) values 0.17 0.27 μM, respectively, transcending anti-COVID-19 drug molnupiravir. The preliminary silico results greatly supported biochemical results, proposing molecule strongly stabilizingly strikes key catalytic pockets RdRp's ExoN's principal sites predictably via nucleoside analogism mode anti-RNA action (since be considered uridine analog). Moreover, idealistic druglikeness pharmacokinetic characteristics make it ready pharmaceutical formulation expected very good clinical behavior caused by COVID-19. To cut short, current critical extension work significantly potentiate S-217622's vitro/in vivo (preclinical) since they showed striking inhibitory novel anti-SARS-CoV-2 Mpro could extended other enzymes RdRp ExoN, unveiling possible use compound next versions virus (i.e., disclosing nonspecific properties almost strain), SARS-CoV-3, encouraging us rapidly start compound's vast evaluations.

Language: Английский

---

Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: March 7, 2023

The new coronavirus SARS-COV-2, which emerged in late 2019 from Wuhan city of China was regarded as causing agent the COVID-19 pandemic. primary protease is also known by various synonymous i.e., main protease, 3-Chymotrypsin-like (3CLPRO) has a vital role replication virus, can be used potential drug target. current study aimed to identify novel phytochemical therapeutics for 3CLPRO machine learning-based virtual screening. A total 4,000 phytochemicals were collected deep literature surveys and other sources. 2D structures these retrieved PubChem database, with use molecular operating environment, descriptors calculated. Machine screening performed predict active against SARS-CoV-2 3CLPRO. Random forest achieved 98% accuracy on train test set among different learning algorithms. model screen leads identification 26 inhibitors These hits then docked into site Based docking scores protein-ligand interactions, MD simulations have been using 100 ns top 5 inhibitors, ivermectin, APO state post-dynamic analysis i.e,. Root means square deviation (RMSD), mean fluctuation (RMSF), MM-GBSA reveal that our newly identified form significant interactions binding pocket stable complexes, indicating could antagonists SARS-COV-2.

Language: Английский

---