Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.

Discovery of highly potent pancoronavirus fusion inhibitors that also effectively inhibit COVID-19 variants from the UK and South Africa

We report the discovery of a series of benzoic acid-based inhibitors that show highly potent pancoronavirus activity. Some compounds also show complete inhibition of CPE (IC100) at 1.25 μM against an authentic SARS-CoV-2 (US_WA-1/2020). Furthermore, the most active inhibitors also potently inhibited variants initially identified in the UK and South Africa. We confirmed that one of the potent inhibitors binds to the prefusion spike protein trimer of SARS-CoV-2 by SPR. Besides, we showed that they inhibit virus-mediated cell-cell fusion. The ADME data show druglike characteristics, and in vivo PK in rats demonstrated excellent half-life (t½) of 11.3 h, mean resident time (MRT) of 14.2 h, and orally bioavailable. Despite the presence of ene-rhodamine moiety, we conclusively demonstrated that these inhibitors target the viral spike protein and are not promiscuous or colloidal aggregators. We expect the lead inhibitors to pave the way for further development to preclinical and clinical candidates.

New Natural Compound Inhibitors of Checkpoint Kinase-1(CHK1) Based on Computational Study

As a malignant tumor of the ovary, the general treatment principle of ovarian cancer is surgical treatment, supplemented by chemotherapy, and some patients can use targeted drugs. Its treatment effect is relatively poor, so the prognosis is poor, the mortality rate is high. To contribute to drug design and refinement, ideal lead compounds with potential inhibitory effects on ATP-competitive CHK1 (Checkpoint kinase-1) inhibitors were downloaded from the drug library (ZINC15 database) and screened afterwards. The ATP-competitive CHK1 inhibitors were identified by using computer-aided virtual screening technology. We first calculated the LibDock score through the docking of proteins and molecules, and then analyzed the pharmacological and toxicological properties. Then, we performed precise docking of the small molecules selected in the above steps with CHK1 protein to analyze their docking mechanism and affinity. Next, we used molecular dynamics simulation to make a assessment if the ligand-CHK1 complex were stable in natural environment. As the result shown, ZINC000008214547 and ZINC000072103632 were proved to bind with CHK1 with a higher binding affinity and stability. Additionally, their toxicological analysis shows that they are less toxic and will not inhibit the activity of cytochrome P-450 2D6. In the simulation of molecular dynamics, we also found that ZINC000008214547-CHK1 and ZINC000072103632-CHK1 complexes’ potential energy were more favorable compared with reference ligand, Prexasertib. Not only that, the two complexes also showed better stability in the natural environment. So, all results elucidated that ZINC000008214547 and ZINC000072103632 were favorable lead inhibitors of CHK1 protein. ZINC000008214547 and ZINC000072103632 were safe and had the potential to inhibit CHK1 protein. They may contribute a solid foundation for the development of CHK1 target drug.

Screening of Common Potential Inhibitors against Periodontitis and Alzheimer's Disease

Introduction: As the amyloid precursor protein performs a remarkable part in chronic periodontitis and the progression of Alzheimer's disease growth, discoveryof novelactive inhibitors of this protein can be of great standing in the treatment of periodontitis. Chronic periodontitis is one of the causative factors and metabolic stressor for diabetes control. In chronic periodontitis and Alzheimer's disease, some molecules have been proposed to inhibit proteins in past. Methods: This study was planned to find present potent inhibitors,A library of KDM compounds was obtained from Chem Div Database. Here, all complexes with goodglide score were short listed for analysis of protein-ligand interaction. Calculations were carried out to estimate the interaction of the ligands selected in complex with the beta amyloid protein. Results: Five top hits were found considering Curcuminas reference. Five small molecules have been proposed as possible inhibitors of this protein. Here in this study, we have focused on small molecule lead inhibitors for identification of Chronic Periodontitis and Alzheimer's disease.

In Silico Functional and Structural Insight of Prenylated Pyrazolocurcumin Derivative Associated with the PGE2 Inhibition through mPGES-1 Blocking

The search of novel mPGES-1 lead inhibitors has recently become subject of interest to medicinal chemists due to the safety in comparison to existing NSAIDs such as coxibs drugs. The recent published work revealed that prenylated pyrazolocurcumin derivative as mPGES-1 has been sucessfully designed and synthesized through computational guided 3D-QSAR approach. To improve our understanding, the present paper aimed to develop in silico functional and structural insight of the compound including pharmacophore mapping, molecular electrostatic potential (MEP) simulation using Density Functional Theory (DFT) and druglikeness prediction associated with PGE2 suppression through mPGES-1 blocking. The data collected from computational modelling studies provide important insight on the molecular conformation and further shed light towards structural modification of the future novel mPGES-1 inhibitors.

Antiviral Drug Discovery To Address the COVID-19 Pandemic

ABSTRACT The magnitude of the morbidity and mortality inflicted upon the global population in less than 1 year has driven the inescapable conclusion that the discovery and development of effective antiviral drugs for COVID-19 are urgent and should be prioritized. The antiviral drug discovery programs that emerged for HIV and hepatitis C virus have enabled technology and expertise to accelerate this process for SARS-CoV-2. The description of candidate lead inhibitors for the viral main protease (Mpro) exemplifies this accelerated approach and reminds us of the needs and opportunities for addressing this pandemic.

Competition NMR for Detection of Hit/Lead Inhibitors of Protein–Protein Interactions

Screening for small-molecule fragments that can lead to potent inhibitors of protein–protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM–mM affinities. Here, we describe an NMR competition assay called w-AIDA-NMR (weak-antagonist induced dissociation assay-NMR), which is sensitive to weak μM–mM ligand–protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex’s protein that is not targeted by the inhibitor, we lower the effective affinity of the complex, allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.

Competition NMR for Detection of Hit/Lead Inhibitors of Protein-Protein Interactions

ABSTRACTScreening for small-molecule fragments that can lead to potent inhibitors of protein-protein interactions (PPIs) is often a laborious step as the fragments cannot dissociate the targeted PPI due to their low μM-mM affinities. Here, we describe an NMR competition assay - called w-AIDA-NMR (weak-Antagonist Induced Dissociation Assay-NMR) - that is sensitive to weak μM-mM ligand-protein interactions and which can be used in initial fragment screening campaigns. By introducing point mutations in the complex’s protein that is not targeted by the inhibitor, we lower the effective affinity of the complex allowing for short fragments to dissociate the complex. We illustrate the method with the compounds that block the Mdm2/X-p53 and PD-1/PD-L1 oncogenic interactions. Targeting the PD-/PD-L1 PPI has profoundly advanced the treatment of different types of cancers.