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Background: Despite tremendous efforts made by scientific community during the outbreak of COVID‐19 pandemic, this disease still remains as a public health concern. Although different types of vaccines were globally used to reduce the mortality, emergence of new variants of SARS‐CoV‐2 is a challenging issue in COVID‐19 pharmacotherapy. In this context, target therapy of SARS‐CoV‐2 by small ligands is a promising strategy. Methods: In this investigation, we applied ligand‐based virtual screening for finding novel molecules based on nirmatrelvir structure. Various criteria including drug‐likeness, ADME, and toxicity properties were applied for filtering the compounds. The selected candidate molecules were subjected to molecular docking and dynamics simulation for predicting the binding mode and binding free energy, respectively. Then the molecules were experimentally evaluated in terms of antiviral activity against SARS‐CoV‐2 and toxicity assessment. Results: The results demonstrated that the identified compounds showed inhibitory activity towards SARS‐CoV‐2 Mpro. Conclusion: In summary, the introduced compounds may provide novel scaffold for further structural modification and optimization with improved anti SARS‐CoV‐2 Mpro activity. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID‐19) as global pandemic disease has been adversely affecting public health and social life with considerable loss of human life worldwide. Therefore, there is an urgent need for developing novel therapeutics to combat COVID‐19. The causative agent of COVID‐19 is SARS‐CoV‐2 which targets human angiotensin converting enzyme 2 (ACE2) as cellular receptor via its spike (S) protein. In this context, interfering with the binding of SARS‐CoV‐2 S protein to target molecules could provide a promising strategy to find novel therapeutic agents against SARS‐CoV‐2. The purpose of the current study was to identify potential peptidomimetics against S protein with a combination of structure‐based virtual screening methods and in vitro assays. Methods: The candidates were inspected in terms of ADME properties, drug‐likeness, as well as toxicity profiles. Additionally, molecular docking and dynamics simulations were performed to predict binding of the studied ligands to spike protein. Results: Biological evaluation of the compounds revealed that PM2 molecule exhibits some antiviral activity. Conclusion: In summary, this study highlights the importance of combining in silico and in vitro techniques in order to identify antiviral compound to tackle COVID‐19 and presents a new scaffold that may be structurally optimized for improved antiviral activity. [ABSTRACT FROM AUTHOR]

Background: RON (Recepteur d′Origine Nantais) receptor tyrosine kinase is a promising target for anti‐cancer therapeutics. The aim of this study was to identify new RON inhibitors using virtual screening methods. Methods: To this end, a ligand‐based virtual screening approach was employed for screening of ZINC database on the homology model of RON receptor. All the selected hits were inspected in terms of drug‐likeness, ADME properties, and toxicity profiles. Ligand‐based similarity searches along with further filtering criteria led to the identification of two compounds, TKI1 and TKI2 that were evaluated using in vitro cell‐based RON inhibition assays. Results: The results showed that TKI1 and TKI2 could reduce phosphorylation of RON. Both compounds showed inhibitory activity of the downstream mTOR pathway with no apparent effects on other signaling mediators in a dose‐dependent manner. Conclusion: These compounds can provide a basis for developing novel anti‐RON inhibitors applicable to cancer therapy using medicinal chemistry‐oriented optimization strategies. [ABSTRACT FROM AUTHOR]

2‐Pyrazoline core is a very interesting five‐membered heterocycle, which has been explored in recent years due to its vast applications as the core structure of bioactive and industrial agents. Based on literature studies, versatile synthetic approaches have been employed for the preparation of 2‐pyrazolines, among them the reaction between hydrazines and α,β‐unsaturated enones as the most used method. In this review article, different methods for the synthesis of 2‐pyrazolines using hydrazine derivatives were classified and presented. Initially, numerous catalytic methods for the preparation of 2‐pyrazolines from hydrazines and α,β‐unsaturated enones are reviewed and various aspects of these methods discussed including catalyst efficiency, catalyst recovery, green chemistry, cost‐effectiveness, scope of the method, enantioselectivity, and yield. In addition, reactions between hydrazines and other reagents in multicomponent and two‐component reactions, developed recently, are discussed. Finally, some of the important applications of 2‐pyrazolines are summarized. [ABSTRACT FROM AUTHOR]

To investigate whether peptide sequences with specific translocation across the gastrointestinal barrier can be identified as drug delivery vehicles, in vivo phage display was conducted. For this purpose, a random library of 12‐mer peptides displayed on M13 bacteriophage was orally administered to mice followed by recovery of the phage particles from the blood samples after three consecutive biopanning rounds. The obtained peptide sequences were analyzed using bioinformatics tools and software. The results demonstrated that M13 bacteriophage bearing peptides translocate nonspecifically across the mice intestinal mucosal barrier deduced from random distribution of amino acids in different positions of the identified peptide sequences. The most probable reason for entering the phage particles into systemic circulation after oral administration of the peptide library can be related to the nanoscale nature of their structures which provides a satisfying platform for the purpose of designing nanocarriers in pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Recently, multi‐target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual‐acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6‐chloro‐N‐methyl‐N‐[3‐(4‐methylpiperazin‐1‐yl)propyl]‐1H‐indole‐2‐carboxamide) and compound 4 (7‐chloro‐N‐[(1‐methylpiperidin‐3‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinoline‐2‐carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy. [ABSTRACT FROM AUTHOR]

Histamine H3 receptors (H3R), belonging to G‐protein coupled receptors (GPCR) class A superfamily, are responsible for modulating the release of histamine as well as of other neurotransmitters by a negative feedback mechanism mainly in the central nervous system (CNS). These receptors have gained increased attention as therapeutic target for several CNS related neurological diseases. In the current study, we aimed to identify novel H3R ligands using in silico virtual screening methods. To this end, a combination of ligand‐ and structure‐based approaches was utilized for screening of ZINC database on the homology model of human H3R. Structural similarity‐ and pharmacophore‐based approaches were employed to generate compound libraries. Various molecular modeling methodologies such as molecular docking and dynamics simulation along with different drug likeness filtering criteria were applied to select anti‐H3R ligands as promising candidate molecules based on different known parent lead compounds. In vitro binding assays of the selected molecules demonstrated three of them being active within the micromolar and submicromolar Ki range. The current integrated computational and experimental methods used in this work can provide new general insights for systematic hit identification for novel anti‐H3R agents from large compound libraries. [ABSTRACT FROM AUTHOR]

Grid-independent descriptors are extensively used in 3D quantitative structure-activity relationship (3D-QSAR) studies. These kinds of descriptors represent the spatial arrangement of the atoms in a 3D fashion. In the current study, we have developed a 3D-QSAR model for a set of hydroxamic acid-based derivatives as tumor necrosis factor-α converting enzyme (TACE) inhibitors. The generated model revealed the importance of some main moieties in the potency of these compounds. Quinolinyl and hydroxamate moieties have the ability to act as hydrogen bond acceptors and hot spot points. On the other hand, phenyl ring can participate in hydrophobic contacts with the receptor. 3D-QSAR analyses resulted in the partial least squares model of 3 latent variables with internal and external validation yielding q2 values of 0.66 and 0.73, respectively. The result of the current study can be used in designing of potent TACE inhibitors where inhibition of TACE enzyme is required, such as inflammatory diseases, atherosclerosis, osteoporosis, autoimmune disorders, allograft rejection, and cancer. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a disease caused by a protozoan parasites belonging to the genus Leishmania. It causes morbidity and mortality in the tropical and subtropical regions. Current drugs are toxic, expensive, and require long-term treatment. Thus, identification and development of novel, cheap, efficient, and safe antileishmanial compounds as drug candidates are important from pharmaceutical point of view. Quantitative structure-activity relationship (QSAR) methods are used to predict the pharmaceutically relevant properties of drug candidates whenever it is applicable. The aim of this study was to use two different techniques, namely multiple linear regression (MLR) and artificial neural networks (ANNs) in predicting the antileishmanial activity (i.e. pIC50) of 5-(5-nitroheteroaryl-2-y1)-1,3,4-thiadiazole derivatives. To this end, genetic algorithm-coupled partial least square and backward multiple regression method were used to select a number of calculated molecular descriptors to be used in MLR and ANN-based QSAR studies. The predictive power of the models was also assessed using leave-one-out and leave-group-out cross validation methods. Also, molecular modeling studies were conducted based on DNA topoisomerase I to identify the binding interactions responsible for antileishmanial activity of those analogs. The results suggest that hydrogen bonding interactions and several hydrophobic interactions of ligands with the active site of Leishmania major topoisomerase IB are responsible for their potent antileishmanial activity. These results can be exploited for structure-based computer-aided drug designing of new and selective leishmania topoisomerase inhibitors. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Peptide phage display, a powerful method for ligand identification, was used to identify new peptide ligands for epidermal growth factor receptor. A-431 cells expressing epidermal growth factor receptor were used as the matrix in a cell-based subtractive biopanning approach using a 7-mer peptide displaying phage library. Two novel peptide ligands were identified and tested for their affinities and functional effects on epidermal growth factor receptor. The identified peptides were able to inhibit the epidermal growth factor-induced phosphorylation of epidermal growth factor receptor in a concentration-dependent manner. The results of affinity binding experiments showed that the natural ligand, that is epidermal growth factor, was able to inhibit competitively the binding of peptide-bearing phage to epidermal growth factor receptor expressing A-431 cells. Molecular modeling studies were used to calculate the free energies for the binding of peptides to the receptor-binding site as well as proposing the interaction modes for this binding. The calculated values for the binding energies were found to be similar to our experimental data and those of previously reported studies. [ABSTRACT FROM AUTHOR]