Pharmacophore Search Research Articles

Identification of FtsZ Interdomain Cleft Effectors Based on Pharmacophore Search and Molecular Docking

Identification of FtsZ Interdomain Cleft Effectors Based on Pharmacophore Search and Molecular Docking

Exploring a repurposed candidate with dual hIDO1/hTDO2 inhibitory potential for anticancer efficacy identified through pharmacophore-based virtual screening and in vitro evaluation

Discovering effective anti-cancer agents poses a formidable challenge given the limited efficacy of current therapeutic modalities against various cancer types due to intrinsic resistance mechanisms. Cancer immunochemotherapy is an alternative strategy for breast cancer treatment and overcoming cancer resistance. Human Indoleamine 2,3-dioxygenase (hIDO1) and human Tryptophan 2,3-dioxygenase 2 (hTDO2) play pivotal roles in tryptophan metabolism, leading to the generation of kynurenine and other bioactive metabolites. This process facilitates the de novo synthesis of Nicotinamide Dinucleotide (NAD), promoting cancer resistance. This study identified a new dual hIDO1/hTDO2 inhibitor using a drug repurposing strategy of FDA-approved drugs. Herein, we delineate the development of a ligand-based pharmacophore model based on a training set of 12 compounds with reported hIDO1/hTDO2 inhibitory activity. We conducted a pharmacophore search followed by high-throughput virtual screening of 2568 FDA-approved drugs against both enzymes, resulting in ten hits, four of them with high potential of dual inhibitory activity. For further in silico and in vitro biological investigation, the anti-hypercholesterolemic drug Pitavastatin deemed the drug of choice in this study. Molecular dynamics (MD) simulations demonstrated that Pitavastatin forms stable complexes with both hIDO1 and hTDO2 receptors, providing a structural basis for its potential therapeutic efficacy. At nanomolar (nM) concentration, it exhibited remarkable in vitro enzyme inhibitory activity against both examined enzymes. Additionally, Pitavastatin demonstrated potent cytotoxic activity against BT-549, MCF-7, and HepG2 cell lines (IC50 = 16.82, 9.52, and 1.84 µM, respectively). Its anticancer activity was primarily due to the induction of G1/S phase arrest as discovered through cell cycle analysis of HepG2 cancer cells. Ultimately, treating HepG2 cancer cells with Pitavastatin affected significant activation of caspase-3 accompanied by down-regulation of cellular apoptotic biomarkers such as IDO, TDO, STAT3, P21, P27, IL-6, and AhR.

Preclinical Development of PNT6555, a Boronic Acid-Based, Fibroblast Activation Protein-α (FAP)-Targeted Radiotheranostic for Imaging and Treatment of FAP-Positive Tumors.

The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N-(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N-(pyridine-4-carbonyl)-d-Ala-boroPro-based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA-FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell-derived tumors expressing mouse FAP; the diagnostic potential of 68Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of 177Lu-, 225Ac-, or 161Tb-chelated analogs using human embryonic kidney cell-derived tumors expressing mouse FAP; and the tumor-selective delivery of 177Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their natGa and natLu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. 68Ga-PNT6555 and 68Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. 177Lu-PNT6555 was distinguished from 177Lu-PNT6952 and 177Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 177Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with 177Lu-PNT6555 producing the greatest tumor growth delay and animal survival. 225Ac-PNT6555 and 161Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer.

Challenges in drug discovery and description targeting Leishmania spp.: enzymes, structural proteins, and transporters

Leishmaniasis is a complex tropical disease caused by the protozoan parasite Leishmania spp. Classical chemotherapy includes pentavalent antimonial; however, pentamidine, amphotericin B, and miltefosine have been used. Chemo-resistance remains a risk for successful treatment; thus, target identification and development of selective drugs remain a priority in controlling this disease. Evidence indicates that 6-phosphogluconate dehydrogenase (6PGDH), β-tubulin protein, and ATP-dependent transporters (ABCs-T) are potential targets to be addressed. The pentose phosphate pathway key enzyme 6PGDH is essential for protecting kinetoplastid parasites from oxidative stress and differs from the mammalian host enzyme (<35% AA sequence identity). An optimized 3D model has been used to select high -affinity compounds toward the enzyme through virtual screening and subsequent evaluation in vivo. In kinetoplasts, tubulins are highly conserved proteins essential for microtubule formation. However, compared to other eukaryotic cells, there is a differential susceptibility of kinetoplastid proteins to antimicrotubular agents, e.g., colchicine resistance. A comparison of experimental models between bovine and Leishmania β-tubulin protein allowed us to identify structural modification products of various amino acid substitutions, which hinder the access of colchicine to the binding pocket of the Leishmania protein. Similar changes are found in the β-tubulin sequence of other kinetoplastids such as Trypanosoma cruzi, T. brucei, and T. evansi. The evaluation of the β-tubulin protein as a therapeutic target and the compounds that selectively interact with it was carried out using in silico approaches. The activities of ABC-Transporters are related to the main causes of drug resistance, and the collected evidence suggests that for the ABC-Transporter blocker glibenclamide, there is a: (1) differential susceptibility of Leishmania spp. vs. macrophages; (2) greater susceptibility of axenic amastigotes vs. promastigotes; and (3) glibenclamide-glucantime synergistic drug interaction in macrophage-infected cells. Herein, we discuss the potential value of designing ABC-Transporter blockers for combination therapy in the treatment of leishmaniasis. The examples mentioned above highlight the importance of the search for new therapeutic targets and pharmacophores for the design of alternative treatments for the disease.

16-Hydroxy-ent-halima-5(10),13-dien-15,16-olide from Polyalthia longifolia targets adipogenesis by inhibiting mitotic clonal expansion and ameliorates dyslipidemia

Obesity-related metabolic disorders are increasing at an alarming rate worldwide. The FDA has approved many molecules for weight loss therapy; most of them act on the gut level by inhibiting lipid uptake or on the central nervous system by controlling appetite. Limitations and drawbacks have propelled the search for new pharmacophores exhibiting favourable metabolic alteration at adipocytes, and natural products have always been there to prove their worth. In our efforts, we have identified 16-hydroxy-ent-halima-5(10),13-dien-15,16-olide (PLH), a halimane diterpene isolated from Polyalthia longifolia, demonstrating anti-adipogenic and anti-dyslipidemic activity. It inhibited adipogenesis in 3T3-L1 preadipocyte and C3H10T1/2 mesenchymal stem cell lines. Furthermore, it decreased set of adipogenic markers at transcript and protein levels. Cell cycle studies indicated that PLH halts the mitotic clonal expansion. Mechanistic studies shows that PLH activate Wnt/β-catenin signaling pathway to inhibit the adipogenesis. The study suggested that PLH inhibited adipogenesis during the early phase of differentiation by targeting mitotic clonal expansion and arresting the cell cycle in the G1 phase of the cell cycle. It improved the dyslipidemic condition in HFD-fed hamsters by decreasing the body weight, fat mass, eWAT weight and improving the serum lipid profile. Overall, PLH has been found as a potential drug candidate and a pharmacophore for combating metabolic disorders including obesity and dyslipidemia.

Orphan GPRC5B activation modulates airway contractility

Background: Multiple asthma phenotypes are driven by pathobiological heterogeneity. Almost 25% of asthma patients do not respond well to current treatments like inhaled corticosteroids, urging researchers and clinicians to propose novel treatment targets and strategies. Orphan type C G-protein coupled receptor GPRC5B is one such novel target abundantly expressed in various tissues, but there are no known ligands for GPRC5B. Previously, we demonstrated that orphan type C G-protein coupled receptor GPRC5B is increasingly expressed in human asthmatic airways and plays a crucial role in regulating intracellular calcium ([Ca 2+ ] i ) in human airway smooth muscle (ASM) cells. However, the role of GPRC5B activation on airway contraction is not identified yet. Our objective for this study is to design and synthesize a novel ligand for GPRC5B and determine the effect of GPRC5B activation on [Ca 2+ ] i responses in ASM cells and airway contractility in ex vivo murine airways. Methods: ZincPharmer was used for pharmacophore search. After energy minimization, the top hit compound was synthesized using a standard amide coupling reaction, purified by flash chromatography, and characterized by NMR spectroscopy. Human ASM cells loaded with Fura-2 AM were imaged for [Ca 2+ ] i responses. Silencer select siRNA was used for transient silencing of GPRC5B in ASM cells. Myosin light chain (MLC) phosphorylation was measured using immunoblot analysis. Precision-cut lung slices (PCLS) (~200 μm thickness) of wild-type C57BL6 mice were used for contractile studies. Results: Based on molecular docking data, the top compound N-(5-chloro-2-hydroxybenzyl)-2-((tetrahydro-2H-pyran-4-yl)oxy) acetamide (L1) was synthesized. Concentration-dependent [Ca 2+ ] i responses were observed on human ASM cells stimulated with L1 (1 nM - 1 μM) that were comparable to the known contractile agonist histamine (10 μM). L1-induced [Ca 2+ ] i response was significantly reduced in GPRC5B knockdown ASM cells. GPRC5B knockdown in ASM cells was verified by Western analysis. Further, L1 exposure increased the MLC phosphorylation (Thr18/Ser19) in human ASM cells compared to vehicle. Acute exposure of L1 (1 μM) increased airway contractility of PCLS (~17%-25%) compared to vehicle exposure. Conclusion: These findings suggest that GPRC5B activation modulates intracellular calcium and airway contractility in human ASM cells and murine PCLS. Thus, GPRC5B could potentially be considered for a novel therapeutic regimen to tackle asthma. This work was partly supported by NIH grants R01-HL146705 (Venkatachalem), R01-HL088029 (Prakash), and R01-HL142061 (Pabelick, Prakash). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Galileo: Three-dimensional searching in large combinatorial fragment spaces on the example of pharmacophores

Fragment spaces are an efficient way to model large chemical spaces using a handful of small fragments and a few connection rules. The development of Enamine’s REAL Space has shown that large spaces of readily available compounds may be created this way. These are several orders of magnitude larger than previous libraries. So far, searching and navigating these spaces is mostly limited to topological approaches. A way to overcome this limitation is optimization via metaheuristics which can be combined with arbitrary scoring functions. Here we present Galileo, a novel Genetic Algorithm to sample fragment spaces. We showcase Galileo in combination with a novel pharmacophore mapping approach, called Phariety, enabling 3D searches in fragment spaces. We estimate the effectiveness of the approach with a small fragment space. Furthermore, we apply Galileo to two pharmacophore searches in the REAL Space, detecting hundreds of compounds fulfilling a HSP90 and a FXIa pharmacophore.

In silico-моделирование в оптимизации алгоритмов фармакокинетических исследований [25MG2+] порфирин-фуллереновых наночастиц

The search for effective pharmacophores to treat ischemic stroke is precipitated by the prevalence and high mortality of the condition. Optimization of preclinical scenarios for promising neuroprotectants by mathematical modeling using up-to-date computational platforms is a well-defined and urgent task. This study aimed to develop a drug-oriented model represented by an ordinary differential equation system to study pharmacokinetics of 25Mg2+-releasing porphyrin-fullerene nanocationite PMC16 in silico using MATLAB and adjust computating model's adequatness using in vivo rat model. The developed five-compartment model predicts the distribution of nanoparticles in organs and tissues (e.g. the brain, the heart and the liver) for the purpose of experimental parameters optimization. The in silico produced pharmacokinetic curves show good agreement with the data obtained using in vivo rat model of ischemic stroke. The in silico and in vivo results indicate that PMC16 nanoparticles effectively cross the blood-brain barrier.

Discovery of Novel Coumarin Derivatives as Potential Dual Inhibitors against α-Glucosidase and α-Amylase for the Management of Post-Prandial Hyperglycemia via Molecular Modelling Approaches.

Coumarin derivatives are proven for their therapeutic uses in several human diseases and disorders such as inflammation, neurodegenerative disorders, cancer, fertility, and microbial infections. Coumarin derivatives and coumarin-based scaffolds gained renewed attention for treating diabetes mellitus. The current decade witnessed the inhibiting potential of coumarin derivatives and coumarin-based scaffolds against α-glucosidase and α-amylase for the management of postprandial hyperglycemia. Hyperglycemia is a condition where an excessive amount of glucose circulates in the bloodstream. It occurs when the body lacks enough insulin or is unable to correctly utilize it. With open-source and free in silico tools, we have investigated novel 80 coumarin derivatives for their inhibitory potential against α-glucosidase and α-amylase and identified a coumarin derivative, CD-59, as a potential dual inhibitor. The ligand-based 3D pharmacophore detection and search is utilized to discover diverse coumarin-like compounds and new chemical scaffolds for the dual inhibition of α-glucosidase and α-amylase. In this regard, four novel coumarin-like compounds from the ZINC database have been discovered as the potential dual inhibitors of α-glucosidase and α-amylase (ZINC02789441 and ZINC40949448 with scaffold thiophenyl chromene carboxamide, ZINC13496808 with triazino indol thio phenylacetamide, and ZINC09781623 with chromenyl thiazole). To summarize, we propose that a coumarin derivative, CD-59, and ZINC02789441 from the ZINC database will serve as potential lead molecules with dual inhibition activity against α-glucosidase and α-amylase, thereby discovering new drugs for the effective management of postprandial hyperglycemia. From the reported scaffold, the synthesis of several novel compounds can also be performed, which can be used for drug discovery.

Azolo[5,1‐c][1,2,4]triazines and Azoloazapurines: Synthesis, Antimicrobial activity and in silico Studies

AbstractThe present work reports on the synthesis of series of azolo[5,1‐c][1,2,4]triazines and derivatives of azoloazapurines. The synthesized compounds were tested in vitro for antibacterial activity against N. gonorrhoeae and antimycotic activity against Trichophyton interdigitale, Epidermophyton floccosum, Microsporum canis and Candida albicans. It was found that 10 compounds of the series of 3‐nitroazolo[5,1‐c][1,2,4]triazine‐4‐amines 4 exhibit high antibacterial activity (MIC≤15 μg/ml), but do not exhibit antimycotic activity. For compounds active against N. gonorrhoeae, a biological target was predicted from the pharmacophore search method and homologous modeling was carried out for it. The results of molecular docking using the constructed model of dihydrofolate reductase have a good correlation with in vitro tests. Refined docking showed the similarity of the leading compounds positions in the protein active site. The formation of stable non‐covalent bonds of the nitro group with the amino acid residues Lys34/Lys55 makes a major contribution to the orienting effect of ligands.

Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer.

The abnormal Wnt signaling pathway leads to a high expression of β-catenin, which causes several types of cancer, particularly colorectal cancer (CRC). The inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment by blocking the Wnt signaling pathway. A pharmacophore search and pharmacophore docking were performed to identify potential TNKS inhibitors in the training databases. The weighted MM/PBSA binding free energy of the docking model was calculated to rank the databases. The reranked results indicated that 26.98% of TNKS inhibitors that were present in the top 5% of compounds in the database and near an ideal value ranked 28.57%. The National Cancer Institute database was selected for formal virtual screening, and 11 potential TNKS inhibitors were identified. An enzyme-based experiment was performed to demonstrate that of the 11 potential TNKS inhibitors, NSC295092 and NSC319963 had the most potential. Finally, Wnt pathway analysis was performed through a cell-based assay, which indicated that NSC319963 is the most likely TNKS inhibitor (pIC50 = 5.59). The antiproliferation assay demonstrated that NSC319963 can decrease colorectal cancer cell growth; therefore, the proposed method successfully identified a novel TNKS inhibitor that can alleviate CRC.

Deciphering the Synergistic Mechanism of Cortistatin towards Cancer Targets Using Network Pharmacology Approach

Abstract: Steroidal alkaloid cortistatin is a promising marine natural compound isolated from marine sponges Corticium simplex. Experimental studies and clinical evidence have shown that cortistatin and its derivatives have a curative effect in patients with autoimmune disorders, HIV infection and several types of cancer. The objective of our study was to examine the potential cancer-related therapeutic objectives of Cortistatin using a network pharmacology method, which is a computational approach, including inverse pharmacophore research, enrichment analysis, molecular docking and dynamics study. Systematic protocol also involves the assessment of ADMET parameters to define the pharmacokinetic profile of cortistatin. Inverse pharmacophore search method was used for computational target fishing and target proteins were ranked based on the graph theory approach. Cancer target proteins, namely HSP90, EGFR, CDK2, MMP13, MAPK13, AR, ESR1, PTPN11 and SRC, were classified as top-ranking proteins according to graph theory parameters, namely MCC, DMNC, MNC, Degree(Local-based methods), EPC, Bottleneck, Eccentricity, Closeness, Radiality, Betweenness, Stress(Global-based methods) and Clustering Coefficient. Enrichment assessment established on Gene Ontology and pathway analysis of these proteins that play a vital role in cancer pathways, FaxO Signalling pathways, Ras Signalling pathways and tyrosine metabolism. Molecular docking and dynamic simulation studies of cortistatin with proposed target proteins were found to be stable and conformers generated after 3ns were consistent with stable inter-molecular interactions. The current study summarized here would provide a broad perspective on the therapeutic potential of cortistatin and provide new insights into the future development of cancer therapy strategies. Key words: Cortistatin, Marine natural product, Molecular docking, Network pharmacology, Cancer targets, Pharmacokinetics.

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases.

In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

From Quinoline to Quinazoline-Based S. aureus NorA Efflux Pump Inhibitors by Coupling a Focused Scaffold Hopping Approach and a Pharmacophore Search.

Antibiotic resistance breakers, such as efflux pump inhibitors (EPIs), represent a powerful alternative to the development of new antimicrobials. Recently, by using previously described EPIs, we developed pharmacophore models able to identify inhibitors of NorA, the most studied efflux pump of Staphylococcus aureus. Herein we report the pharmacophore‐based virtual screening of a library of new potential NorA EPIs generated by an in‐silico scaffold hopping approach of the quinoline core. After chemical synthesis and biological evaluation of the best virtual hits, we found the quinazoline core as the best performing scaffold. Accordingly, we designed and synthesized a series of functionalized 2‐arylquinazolines, which were further evaluated as NorA EPIs. Four of them exhibited a strong synergism with ciprofloxacin and a good inhibition of ethidium bromide efflux on resistant S. aureus strains coupled with low cytotoxicity against human cell lines, thus highlighting a promising safety profile.

Recent Advances in Synthesis and Biological Assessment of Quinoline‐Oxygen Heterocycle Hybrids

AbstractThe exploration of hybrid molecules for targeting various diseases represents a highly promising approach which has showcased significant momentum worldwide, in the last two decades. Diversely substituted quinoline scaffolds present in naturally occurring bioactive compounds, signify their role in various biological processes and stimulated the research developments around it, for diverse therapeutic applications. With the ongoing search for suitable pharmacophores, the quinoline derivatives have emerged as versatile compounds possessing significant and broad spectrum of biological activities. Further, conjugation of quinoline with other bioactive heterocycles containing oxygen yielded hybrid organic frameworks with improved therapeutic profile leading to an emerging paradigm and tremendous growth in the contemporary drug discovery regime. The synthesis of these hybrid skeletons with high efficiency still remains the most strenuous task and a lot of research work is being performed in this direction. In the present article, we have reviewed the synthetic protocols leading to quinoline‐oxygen heterocycle hybrids and also highlighted the systematic and biological assessment of developed pharmacophores.

Computational investigation of novel farnesyltransferase inhibitors using 3D-QSAR pharmacophore modeling, virtual screening, molecular docking and molecular dynamics simulation studies: A new insight into cancer treatment

Farnesyltransferase (FTase) is considered as an effective target in treating a variety of cancers. In this investigation, a 3D-QSAR pharmacophore search was performed to identify potential inhibitors against FTase. Correspondingly, 3D-QSAR pharmacophore models for FTase inhibitors were generated utilizing the training set compounds and validated through the test set, cost analysis and Fischer's randomization test. The created pharmacophore models were evaluated based on Debnath's analysis. Then, the pharmacophore model Hypo1 was selected to perform pharmacophore-based screening. Subsequently, the identified compounds were filtered considering Lipinski's Rule of Five (RoF) and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. In the next step, the inter-molecular interactions of the retrieved compounds and the most active compound of the training set with FTase were analyzed utilizing the flexible docking technique. Eventually, the best two compounds, ZINC08952683 and ZINC08918035, along with the reference compound, ZINC13559176, were selected for Molecular Dynamics (MD) studies in order to conduct an in-depth study on their complexes with FTase. MD results confirmed docking studies and showed that these two compounds could make stable complexes with the FTase active site and may have great inhibitory effects on FTase.

Machine learning and pharmacophore‐based prediction of allosteric modulators of Nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors are important members of the ligand-gated ion channel family. They participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. Recent experimental results of electrophysiological studies indicate that apigenin tested on the function of the a7-subunit of the human nicotinic acetylcholine (a7-nACh) receptor caused a potentiation of currents induced by acetylcholine and works as positive allosteric modulator (PAM). Mechanism of action by which apigenin interact with the nicotinic acetylcholine (a7-nAChR) receptor is not fully understood. Using computational modeling techniques, such as pharmacophore search, molecular docking and molecular dynamics we have identified location of inter-subunit binding for apigenin in transmembrane region. Using machine learning methodologies, we identified several novel apigenin analogs that may work as positive allosteric modulators.

Химико-токсикологическая оценка опасности при обращении с ракетным топливом 2-диметиламиноэтилазидом и его производными

The hazard was studied related to toxic effects on the production personnel of the aerospace industry for the experimental rocket fuels of 2-dimethylaminoethylazide and its derivatives — 2-azido-N-methylethanamine and 2-azido-N-cyclopropylethanamine used for liquid propellant rocket engines. The calculation and analysis of physical and chemical constants that characterize the bioavailability of substances based on the rules of N.V. Lazarev, С.A. Lipinsky, and S.M. Jorgensen are made. Pharmacophore analysis and search for active sites of a number of receptors related to carcinogenesis, psychotropic and nerve processes, and the cardiovascular system were performed in the Schrödinger software package. Molecular docking of the receptors and the studied compounds was performed, and the results were analyzed in AutoDock Vina. The values are determined concerning approximately safe exposure levels, hazard classes of substances, and the maximum possible concentrations (volatility) of the rocket fuels that occur in the event of an emergency leak. Through the use of probit method the assessment was related to the immediate non-carcinogenic health risks that service personnel are exposed to in the event of accidental fuel leaks (irritating effect, diseases of the respiratory, nervous, and cardiovascular systems). The results have practical application in the search and synthesis of the rocket fuels - safe analogues of the more toxic heptyl (1,1-dimethylhydrazine), the use of which leads to the development of occupational diseases in the operating personnel and environmental pollution by the aerospace industry facilities.

Pharmacophore Investigations of Potential COVID-19 RNA Polymerase (Rdrp) Inhibitors: Repurposing FDA-Approved Drugs

Authors: Valentina L. Kouznetsova, Caroline Kellogg, Aidan Zhang, Mahidhar Tatineni, Mark A. Miller, Igor F. Tsigelny Background: SARS-CoV-2 has caused tens of millions of infections worldwide and millions of deaths. Currently, no effective treatment has been identified against the virus. Of its viral proteins, the RNA-dependent RNA polymerase (RdRp) is a promising target for drug design because of its importance in the replication of the virus. Material and Methods: After the identification of an RdRp pocket site based on the crystal structure of the RdRp– nsp7–nsp8 complex and the triphosphate form of remdesivir (PDB ID: 7BV2), we created a pharmacophore model consisting of 11 different features. These features include two acceptors, three donors, one acceptor and donor, three donor or acceptor, and one hydrophobic; an excluded volume of R=1.1 Å was also added. We then ran a pharmacophore search on our conformational database (DB) of approximately 2500 FDA-approved drugs and 600 000 conformations to identify potential drug-candidates. To determine the drugs that bound the best, we conducted multi conformational docking of these results to the previously identified pocket site. Results: The pharmacophore search found 315 different potential inhibitors of RdRp, of which 85 were chosen based on the number of H-bonds and hydrophobic interactions in the best docking pose. Several of the drugs selected, including ritonavir, dasatinib, imatinib, and sofosbuvir, have previously been shown to be effective against other viruses. Conclusions: These findings highlight compounds that could lead to both in vitro and in vivo studies to identify potential treatments against SARS-CoV-2.

Diaminoimidazopyrimidines: Access via the Groebke–Blackburn–Bienaymé Reaction and Structural Data Mining

Imidazopyrimidines with diverse substitution patterns are a prime class of heterocycles, present in many commercially available or late‐stage clinical trials drugs. Here, we describe a fast access to diaminoimidazopyrimidines by means of a powerful multicomponent reaction; the Groebke–Blackburn–Bienaymé reaction. We provide the design of such libraries of compounds, identifying all the structural motifs, and subsequently their synthesis. Scope and limitations are discussed, in addition to data mining in the Cambridge Structural Database and pharmacophore search with Crossminer. The presented approach highlights the vast amount of data available in the databases and provides potential future scaffold hopping alternatives for compounds with similar binding patterns. Further studies are ongoing to introduce more “drug‐like” properties into this scaffold and to investigate cellular mechanism‐based anti‐cancer behaviours.