Delving into the Latest Updates on Lomibuvir with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Lomibuvir (USAN/INN)

Target

NS5B polymerase

Action

inhibitors

Mechanism

NS5B polymerase inhibitors(Hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System DisordersOther Diseases

Active Indication-

Inactive Indication

Chronic hepatitis C genotype 1Fibrosis

Originator Organization

Vertex Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Vertex Pharmaceuticals, Inc.

License Organization

Vertex Pharmaceuticals, Inc.

Trek Therapeutics PBC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC25H35NO4S

InChIKeyWPMJNLCLKAKMLA-VVPTUSLJSA-N

CAS Registry1026785-55-6

In this COVID-19 pandemic situation, an appropriate drug is urgent to fight against this infectious disease to save lives and prevent mortality. Repurposed drugs and vaccines are the immediate solutions for this medical emergency until discover a new drug to treat this disease. As of now, no specific drug is available to cure this disease completely. Several drug targets were identified in SARS-CoV-2, in which RdRp protein is one of the potential targets to inhibit this virus infection. In-Silico studies plays a vital role to understand the binding nature of the drugs at the atomic level against the disease targets. The present study explores the binding mechanism of reported 53 nucleoside and non-nucleoside RdRp inhibitors and Ivermectin which are in clinical trials. These molecules were screened by molecular docking simulation; in which, the molecules are showing high binding affinity and forming interactions with the key amino acids of active site of RdRp protein are chosen for molecular dynamics simulation (MD) and binding free energy analysis. The results of molecular docking and MD simulation studies reveal that IDX184 is a stable molecule and forms strong interactions with the key amino acids and shows high binding affinity towards RdRp. Hence, IDX184 may also be considered as a potential inhibitor of RdRp after clinical study.Communicated by Ramaswamy H. Sarma.

08 May 2023·Journal of Chemical Information and Modeling

AI-Driven Discovery of SARS-CoV-2 Main Protease Fragment-like Inhibitors with Antiviral Activity In Vitro

Article

Author: Owen, C. David ; Strain-Damerell, Claire ; Saramago, Luiz Carlos ; Ferreira, Vivian Neuza dos Santos ; dos Santos Rosa, Alice ; Tucci, Amanda Resende ; Silva-Junior, Floriano Paes ; Walsh, Martin Austin ; Oliveira Borges, Pedro Henrique ; Lukacik, Petra ; Gomes, Bárbara Figueira ; Dias Miranda, Milene ; Ferreira, Sabrina Baptista ; Senger, Mario R. ; Dantas, Rafael Ferreira ; Santana, Marcos V.

SARS-CoV-2 is the causative agent of COVID-19 and is responsible for the current global pandemic. The viral genome contains 5 major open reading frames of which the largest ORF1ab codes for two polyproteins, pp1ab and pp1a, which are subsequently cleaved into 16 nonstructural proteins (nsp) by two viral cysteine proteases encoded within the polyproteins. The main protease (Mpro, nsp5) cleaves the majority of the nsp's, making it essential for viral replication and has been successfully targeted for the development of antivirals. The first oral Mpro inhibitor, nirmatrelvir, was approved for treatment of COVID-19 in late December 2021 in combination with ritonavir as Paxlovid. Increasing the arsenal of antivirals and development of protease inhibitors and other antivirals with a varied mode of action remains a priority to reduce the likelihood for resistance emerging. Here, we report results from an artificial intelligence-driven approach followed by in vitro validation, allowing the identification of five fragment-like Mpro inhibitors with IC₅₀ values ranging from 1.5 to 241 μM. The three most potent molecules (compounds 818, 737, and 183) were tested against SARS-CoV-2 by in vitro replication in Vero E6 and Calu-3 cells. Compound 818 was active in both cell models with an EC₅₀ value comparable to its measured IC₅₀ value. On the other hand, compounds 737 and 183 were only active in Calu-3, a preclinical model of respiratory cells, showing selective indexes twice as high as those for compound 818. We also show that our in silico methodology was successful in identifying both reversible and covalent inhibitors. For instance, compound 818 is a reversible chloromethylamide analogue of 8-methyl-γ-carboline, while compound 737 is an N-pyridyl-isatin that covalently inhibits Mpro. Given the small molecular weights of these fragments, their high binding efficiency in vitro and efficacy in blocking viral replication, these compounds represent good starting points for the development of potent lead molecules targeting the Mpro of SARS-CoV-2.

01 May 2023·Chemical and Pharmaceutical Bulletin

Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals

Article

Author: Hata, Masayuki ; Hoshino, Tyuji ; Yamamoto, Norio ; Miwa, Kazunori ; Guo, Yan

Computational screening is one of the fundamental techniques in drug discovery. Each compound in a chemical database is bound to the target protein in virtual, and candidate compounds are selected from the binding scores. In this work, we carried out combinational computation of docking simulation to generate binding poses and molecular mechanics calculation to estimate binding scores. The coronavirus infectious disease has spread worldwide, and effective chemotherapy is strongly required. The viral 3-chymotrypsin-like (3CL) protease is a good target of low molecular-weight inhibitors. Hence, computational screening was performed to search for inhibitory compounds acting on the 3CL protease. As a preliminary assessment of the performance of this approach, we used 51 compounds for which inhibitory activity had already been confirmed. Docking simulations and molecular mechanics calculations were performed to evaluate binding scores. The preliminary evaluation suggested that our approach successfully selected the inhibitory compounds identified by the experiments. The same approach was applied to 8820 compounds in a database consisting of approved and investigational chemicals. Hence, docking simulations, molecular mechanics calculations, and re-evaluation of binding scores including solvation effects were performed, and the top 200 poses were selected as candidates for experimental assays. Consequently, 25 compounds were chosen for in vitro measurement of the enzymatic inhibitory activity. From the enzymatic assay, 5 compounds were identified to have inhibitory activities against the 3CL protease. The present work demonstrated the feasibility of a combination of docking simulation and molecular mechanics calculation for practical use in computational virtual screening.

100 Deals associated with Lomibuvir

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External Link

KEGG	Wiki	ATC	Drug Bank
D10425	-	-	DB11954

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Phase 2	United Kingdom	Vertex Pharmaceuticals, Inc.	01 Feb 2012
Fibrosis	Phase 2	United States	Vertex Pharmaceuticals, Inc.	01 Feb 2012
Fibrosis	Phase 2	Germany	Vertex Pharmaceuticals, Inc.	01 Feb 2012
Fibrosis	Phase 2	Canada	Vertex Pharmaceuticals, Inc.	01 Feb 2012
Fibrosis	Phase 2	Poland	Vertex Pharmaceuticals, Inc.	01 Feb 2012
Chronic hepatitis C genotype 1	Phase 2	New Zealand	Vertex Pharmaceuticals, Inc.	01 Aug 2010
Chronic hepatitis C genotype 1	Phase 2	United States	Vertex Pharmaceuticals, Inc.	01 Aug 2010
Chronic hepatitis C genotype 1	Phase 2	New Zealand	Vertex Pharmaceuticals, Inc.	01 Aug 2010
Chronic hepatitis C genotype 1	Phase 2	United States	Vertex Pharmaceuticals, Inc.	01 Aug 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01080222 (ZENITH, Pubmed \| Eur J Gastroenterol Hepatol)	Phase 2	Hepatitis C	152	VX-222+telaprevir	(lomskvjael) = jrwexzyzhy hkfrglvrar (pavrgzoufa )	-	01 Jul 2014
				VX-222+telaprevir+ribavirin	(lomskvjael) = caxroqizay hkfrglvrar (pavrgzoufa )