A combination of structure-based virtual screening and experimental strategies to identify the potency of caffeic acid ester derivatives as SARS-CoV-2 3CL inhibitor from an in-house database.

Drug development requires significant time and resources, and computer-aided drug discovery techniques that integrate chemical and biological spaces offer valuable tools for the process. This study focused on the field of COVID-19 therapeutics and aimed to identify new active non-covalent inhibitors for 3CL, a key protein target. By combining in silico and in vitro approaches, an in-house database was utilized to identify potential inhibitors.

Pre-training strategy for antiviral drug screening with low-data graph neural network: A case study in HIV-1 K103N reverse transcriptase.

Graph neural networks (GNN) offer an alternative approach to boost the screening effectiveness in drug discovery. However, their efficacy is often hindered by limited datasets. To address this limitation, we introduced a robust GNN training framework, applied to various chemical databases to identify potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) against the challenging K103N-mutated HIV-1 RT.

In vitro and in silico studies of the inclusion complexation of 8-bromobaicalein with β-cyclodextrins.

Baicalein, a flavone derived from Scutellaria baicalensis Georgi, exhibits potent anti-inflammatory, antiviral, and anticancer properties. Its derivative, known as 8-bromobaicalein (BB), has been found to have strong cytotoxic effect on MCF-7 human breast cancer cells. However, its limited solubility in water has hindered its potential for wider applications.

Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various β-cyclodextrin derivatives using advanced computational techniques and experimental validation.

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with β-cyclodextrin (βCD) and its three analogs, dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD), were investigated using in silico and in vitro studies.

Enhancing solubility and stability of piperine using β-cyclodextrin derivatives: computational and experimental investigations.

Piperine (PP), a natural alkaloid found in black pepper, possesses significant bioactivities. However, its use in pharmaceutical applications is hindered by low water solubility and susceptibility to UV light degradation. To overcome these challenges, we investigated the potential of β-cyclodextrin (βCD) and its derivatives with dimethyl (DMβCD), hydroxy-propyl (HPβCD) and sulfobutyl-ether (SBEβCD) substitutions to enhance the solubility and stability of PP.

Biochemical and structural comparisons of non-nucleoside reverse transcriptase inhibitors against feline and human immunodeficiency viruses.

Background: Feline immunodeficiency virus (FIV) causes an acquired immunodeficiency-like syndrome in cats. FIV is latent. No effective treatment has been developed for treatment the infected cats.

Computational design of novel nanobodies targeting the receptor binding domain of variants of concern of SARS-CoV-2.

The COVID-19 pandemic has created an urgent need for effective therapeutic and diagnostic strategies to manage the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the emergence of numerous variants of concern (VOCs) has made it challenging to develop targeted therapies that are broadly specific in neutralizing the virus. In this study, we aimed to develop neutralizing nanobodies (Nbs) using computational techniques that can effectively neutralize the receptor-binding domain (RBD) of SARS-CoV-2 VOCs.

Enhancing solubility and stability of sorafenib through cyclodextrin-based inclusion complexation: and studies.

Sorafenib (SOR) is an oral multikinase inhibitor that effectively hampers the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, SOR tablets (Nexavar) have limited oral bioavailability, ranging from 38% to 49%, due to their low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study.

Stability improvement of UV-filter between methoxy cinnamic acid derivatives and cyclodextrins inclusion complexes based on DFT and TD-DFT investigations.

Structures and UV-vis absorption spectra of the host-guest interaction of the methoxy cinnamic acid (MCA) derivatives and cyclodextrins (CDs) were performed by using the density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. All geometries of MCA derivatives (4-MCA, 245-MCA, 246-MCA), three types of CD (αCD, βCD, γCD), and five host-guest inclusion complexes between MCA and CD consisting of 4-MCA/αCD (1), 4-MCA/βCD (2), 245-MCA/βCD (3), 246-MCA/βCD (4), and 246-MCA/γCD (5) were fully optimized by using the M06-2X/6-31G (d,p) levels of theory. Two orientations (A and B) of the MCA guest molecule were considered.

Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CL through Structure-Based Virtual Screening and Experimental Approaches.

3CL is a viable target for developing antiviral therapies against the coronavirus. With the urgent need to find new possible inhibitors, a structure-based virtual screening approach was developed. This study recognized 75 pharmacologically bioactive compounds from our in-house library of 1052 natural product-based compounds that satisfied drug-likeness criteria and exhibited good bioavailability and membrane permeability.

Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study.

The polymyxin colistin is a last line antibiotic for extensively resistant Gram-negative bacteria. Colistin binding to lipid A disrupts the Gram-negative outer membrane, but mobile colistin resistance () gene family members confer resistance by catalyzing phosphoethanolamine (PEA) transfer onto lipid A, neutralizing its negative charge to reduce colistin interactions. Multiple isoforms have been identified in clinical and environmental isolates, with being the most widespread and being common in South and East Asia.

In Vitro and In Silico Study on the Molecular Encapsulation of α-Tocopherol in a Large-Ring Cyclodextrin.

α-tocopherol is the physiologically most active form of vitamin E, with numerous biological activities, such as significant antioxidant activity, anticancer capabilities, and anti-aging properties. However, its low water solubility has limited its potential use in the food, cosmetic, and pharmaceutical industries. One possible strategy for addressing this issue is the use of a supramolecular complex with large-ring cyclodextrins (LR-CDs).

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases.

Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases.

Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening.

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme.

Effect of Water Microsolvation on the Excited-State Proton Transfer of 3-Hydroxyflavone Enclosed in γ-Cyclodextrin.

The effect of microsolvation on excited-state proton transfer (ESPT) reaction of 3-hydroxyflavone (3HF) and its inclusion complex with γ-cyclodextrin (γ-CD) was studied using computational approaches. From molecular dynamics simulations, two possible inclusion complexes formed by the chromone ring (C-ring, Form I) and the phenyl ring (P-ring, Form II) of 3HF insertion to γ-CD were observed. Form II is likely more stable because of lower fluctuation of 3HF inside the hydrophobic cavity and lower water accessibility to the encapsulated 3HF.

Delivery of Alpha-Mangostin Using Cyclodextrins through a Biological Membrane: Molecular Dynamics Simulation.

α-Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (βCDs), particularly with the native βCD and/or its derivative 2,6-dimethyl-β-CD (DMβCD) is a promising technique.

Structural dynamics and susceptibility of anti-HIV drugs against HBV reverse transcriptase.

Hepatitis B virus (HBV), a small enveloped DNA virus, attacks the human liver causing both acute and chronic diseases. Current therapeutic drugs use the nucleos(t)ide analogues (NAs) as a competitive inhibitor against HBV reverse transcriptase (HBV-RT), an essential enzyme pivotally involved in viral replication. Unfortunately, this treatment still causes the development of resistant variants of HBV against NAs.

Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases.

Janus kinases (JAKs) are enzymes involved in signaling pathways that affect hematopoiesis and immune cell functions. JAK1, JAK2, and JAK3 play different roles in numerous diseases of the immune system and have also been considered as potential targets for cancer therapy. In the present study, the susceptibility of the oral JAK inhibitor tofacitinib against these three JAKs was elucidated using the 500-ns molecular dynamics (MD) simulations and free energy calculations based on MM-PB(GB)SA, QM/MM-GBSA (PM3 and SCC-DFTB), and SIE methods.

Cavity Closure of 2-Hydroxypropyl-β-Cyclodextrin: Replica Exchange Molecular Dynamics Simulations.

2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. An understanding of the structural properties of HPβCD and its derivatives, based on the number of 2-hydroxypropyl (HP) substituents at the α-d-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution, called 6-HPβCDs and 2,6-HPβCDs, respectively.

Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors.

Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition.

Interactions of HLA-DR and Topoisomerase I Epitope Modulated Genetic Risk for Systemic Sclerosis.

The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific alleles of human leukocyte antigen (HLA)-DR has been observed among various ethnics. The anti-Topoisomerase 1 antibody is a common autoantibody in SSc with diffuse cutaneous scleroderma, which is one of the clinical subtypes of SSc. On the other hand, an immunodominant peptide of topoisomerase 1 (Top1) self-protein (residues 349-368) was reported to have strong association with ATASSc.

Computational screening of chalcones acting against topoisomerase IIα and their cytotoxicity towards cancer cell lines.

Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIα by computational techniques, and subsequently tested for their in vitro cytotoxicity.

Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and β-Cyclodextrins.

Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti-viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with β-cyclodextrin (βCD) and its derivatives, heptakis-(2,6-di--methyl)-β-cyclodextrin (2,6-DMβCD) and (2-hydroxypropyl)-β-cyclodextrin (HPβCD).

Molecular dynamics simulations of asymmetric heterodimers of HER1/HER2 complexes.

The family of human epidermal growth factor receptors (HER) is involved in tumor cell growth. Homodimerization and heterodimerization of the HER family are important for activation of these receptors. The structures of homodimer conformation are well characterized, while the structures of heterodimer conformations, especially between HER1 and HER2, are not completely understood.