Synthetic Approaches to the New Drugs Approved During 2022

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(6), P. 4376 - 4418

Published: March 15, 2024

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes synthetic approach demonstrated on largest scale for each drug based patent or primary literature. The routes highlight practical methods to construct molecules, sometimes manufacturing scale, access drugs. Ten additional in 2021 one 2020 are included that not covered previous year's review.

Language: Английский

---

Dihydropyrimidine-2-thione derivatives as SARS-CoV-2 main protease inhibitors: synthesis, SAR and in vitro profiling

RSC Advances, Journal Year: 2025, Volume and Issue: 15(8), P. 6424 - 6440

Published: Jan. 1, 2025

Despite the passage of approximately five years since outbreak, an efficacious remedy for SARS-CoV-2 remains elusive, highlighting urgent imperative developing potent inhibitors.

Language: Английский

---

Structural review of SARS-CoV-2 antiviral targets

Structure, Journal Year: 2024, Volume and Issue: 32(9), P. 1301 - 1321

Published: Sept. 1, 2024

Language: Английский

---

Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 11

Published: Nov. 18, 2023

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents substantial threat to health, especially in nations. Given no FDA-approved specific therapy for MERS exists, designing and discovering potent antiviral MERS-CoV crucial. One pivotal strategy inhibiting replication focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting cherry-picked molecules from literature. key features URDL include synthetic tractability (1-2 pot synthesis) scaffold unexplored chemical space. hits were ranked based docking score, MM-GBSA free energy binding, interaction pattern with active site residues. A molecular dynamics (MD) simulation study was performed first two top-ranked compounds analyze stability binding mechanics Poisson-Boltzmann surface area. mean force calculated steered (SMD) simulations indicates improved H-bond potential, enhanced conformational stability, affinity toward target, compared cocrystallized ligand. discovered represent synthetically tractable scaffolds as inhibitors.Communicated by Ramaswamy H. Sarma.

Language: Английский

---

Computational Estimation of Residues Involving Resistance to the SARS-CoV-2 Main Protease Inhibitor Ensitrelvir Based on Virtual Alanine Scan of the Active Site

Biological and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 47(5), P. 967 - 977

Published: May 16, 2024

Ensitrelvir is a noncovalent inhibitor of the main protease (Mpro) severe acute respiratory syndrome coronavirus 2. Acquisition drug resistance in virus-derived proteins serious therapeutic concern, and occurs due to amino acid mutations. In this study, we computationally constructed 24 mutants, which one residue around active site was replaced with alanine performed molecular dynamics simulations complex Mpro ensitrelvir predict residues involved resistance. We evaluated changes entire protein structure ligand configuration each these mutants estimated were recognition. This method called virtual scan. nine (S1A, T26A, H41A, M49A, L141A, H163A, E166A, V186A, R188A), although catalytic dyad (cysteine (Cys)145 histidine (His)41) not significantly moved, changed. Thus, it considered that did recognize while maintaining enzymatic activities, Ser1, Thr26, His41, Met49, Leu141, His163, Glu166, Val186, Arg188 may be related The shift noted M49A similar observed M49I, has been shown experimentally resistant. These findings suggest our research approach can mutations incite

Language: Английский

---

Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study

hLife, Journal Year: 2024, Volume and Issue: 2(8), P. 419 - 433

Published: June 15, 2024

During the continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Omicron variant concern emerged in second half 2021 and has been dominant since November that year. Along with its sublineages, it maintained a prominent role ever since. The Nsp5 main protease (Mpro) virus is characterized by single mutation, P132H. Here we determined X-ray crystal structures P132H mutant (or O-Mpro) as free enzyme complex Mpro inhibitor, alpha-ketoamide 13b-K, conducted enzymological, biophysical well theoretical studies to characterize O-Mpro. We found O-Mpro similar overall structure binding 13b-K; however, displays lower enzymatic activity thermal stability compared WT-Mpro (with "WT" referring prototype strain). Intriguingly, imidazole ring His132 carboxylate plane Glu240 are stacked configuration here. Empirical folding energy calculations suggest dimer destabilized relative due less favorable van der Waals interactions backbone conformations individual protomers. All-atom continuous constant-pH molecular dynamics (MD) simulations reveal display coupled titration. At pH 7, predominantly neutral respect which charged. In order examine whether mutation eases emergence further mutations, also analyzed P132H+T169S double mutant, characteristic BA.1.1.2 lineage. However, little evidence correlation between two sites.

Language: Английский

---

An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 31, 2024

ABSTRACT This manuscript describes the application of Isothermal Titration Calorimetry (ITC) to characterize kinetics 3CL pro from Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and its inhibition by Ensitrelvir, a known non-covalent inhibitor. is main protease that plays crucial role producing whole array proteins necessary for viral infection caused spread COVID-19, responsible millions deaths worldwide as well global economic healthcare crises in recent years. The proposed calorimetric method proved have several advantages over two types enzymatic assays so far applied this system, namely Förster Resonance Energy Transfer (FRET) Liquid Chromatography-Mass Spectrometry (LC-MS). developed ITC-based assay provided rapid response activity, which was used directly derive kinetic constants K M k cat reliably reproducibly, their temperature dependence, activation energy reaction obtained first time. further revealed existence modes competitive mode previously inferred crystallography an unprecedented uncompetitive mode, yielding respective with high precision. described paper thus be generally widely discovery development drugs targeting .

Language: Английский

---

Profiling of coronaviral M^pro and enteroviral 3C^pro specificity provides a framework for the development of broad‐spectrum antiviral compounds

Protein Science, Journal Year: 2024, Volume and Issue: 33(9)

Published: Aug. 16, 2024

The main protease from coronaviruses and the 3C enteroviruses play a crucial role in processing viral polyproteins, making them attractive targets for development of antiviral agents. In this study, we employed combinatorial chemistry approach-HyCoSuL-to compare substrate specificity profiles proteases alphacoronaviruses, betacoronaviruses, enteroviruses. obtained data demonstrate that coronavirus M

Language: Английский

---

An isothermal calorimetry assay for determining steady state kinetic and Ensitrelvir inhibition parameters for SARS-CoV-2 3CL-protease

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 31, 2024

Language: Английский

---