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This study aimed to show how the amount of liquid in a liquid mixture separates, and how it relates to the science of heat and energy.We did experiments to study the liquid phase separation, as well as the ability of drug-like molecules to dissolve in crystal form. The CLME equation was derived based on how heat and energy affect things, like how much substance can dissolve in a liquid, how strong the concentration is, and the temperature at which it melts [denoted as Tm]. The equation is [𝑙𝑜𝑔10 =𝑙𝑜𝑔10 −0.0095 [𝑇𝑚−310] for 310 K. The scientists tested 31 drugs by changing the pH or solvent of the substance and using lasers to see if there were any changes in how they looked. To ensure the material didn't form crystals within 10 seconds, I used a special microscope that utilizes polarized light to conduct some tests.The measured and calculated values showed a strong similarity [with a small error of 0. 40 log units]. The average error was 0. 32 log units.

Background: Acute myeloid leukemia (AML) is a deadly cancer. B cell lymphoma 2 (BCL2) is frequently upregulated in AML and plays a vital role in the viability of both AML and AML stem cells. This study aimed to identify novel phytochemicals against BCL2 and evaluate their pharmacokinetics and toxicity prediction using in-silico tools. Methods: In-silico screening of phytochemicals against BCL2 active site using the PyRx0.8 AutoDock tool, followed by in silico pharmacokinetic and toxicity predictions was performed. Protein-protein interaction analysis was performed using the STRING database for assessing the interactions between BCL2 and neighboring interacting proteins. Results: In total, 1106 terpenoid compounds were screened to evaluate their binding affinity toward BCL2. Five natural compounds demonstrated strong binding to the BCL2 protein after extensive screening, detailed interaction analysis, and visual inspections. Notably, these compounds had higher binding energies than the positive control (venetoclax). In addition, these compounds were found to bind to key BCL2 residues and possess good drug-like properties. Conclusions: The identified phytochemicals represent an important initial step in drug discovery for AML management. Experimental validation is required to optimize the identified phytochemicals as potential BCL2 inhibitors. [ABSTRACT FROM AUTHOR]

Quantitative structure-activity relationship study was used to investigate the relationship between anti-pfdhfr activity and structure of twenty-eight 1,3,5-triazine derivatives. We performed benchmark studies on the molecular geometry, electron properties of 1,3,5-triazine using semi-empirical(PM3), density functional theory and post Hartree-Fock methods. Followed by a QSAR study using multiple linear regression (MLR) and artificial neural networks (ANN). The QSAR models developed allow identify/describe the relationship between the biological activity of the molecules and their molecular descriptors (topological, physicochemical, electronic...). A further external set of compounds was used for validation where a high correlation between experimental and predicted anti-pfdhfr activity values is noticed. This QSAR study provides useful information for developing novel pfdhfr inhibitors. The set's ADME properties and drug similarities, as well as newly produced compounds and reference ligand, were investigated. These findings would be extremely useful in guiding optimization for the development of new anti-pfdhfr drug candidates. [ABSTRACT FROM AUTHOR]

الملخص: أهداف البحث: كان سرطان الرئة ذو الخلايا غير الصغيرة هو النوع الشائع والقاتل من سرطانات الرئة مع ما يقرب من 1.8 مليون حالة ومعدل البقاء على قيد الحياة أقل من 20 ٪ في كل 5 سنوات بعد التشخيص. الهدف من هذا البحث هو تحديد العوامل العلاجية المحتملة لخلايا سرطان الرئة ذو الخلايا غير الصغيرة الحاملة لمستقبلات عامل النمو الأدمي من خلال استخدام بعض التقنيات بمساعدة الكمبيوتر. طرق البحث: تم استخدام تقنية النمذجة الجزيئية التي تقيس علاقة الهيكل بالنشاط الكمي ثنائية الأبعاد على بعض العوامل العلاجية المحتملة على سرطان الرئة ذو الخلايا غير الصغيرة لتطوير نموذج تنبؤي عالي للغاية. تم إجراء فحص افتراضي للالتحام الجزيئي على نفس مجموعة المركبات لتحديد مركبات الإصابة المحتملة. علاوة على ذلك، تم تقييم الميزات الشبيهة بالدواء والحركية الدوائية لأفضل النتائج باستخدام خوادم الويب ''سويس أدمي'' و بي كي سي اس ام''؛ على التوالي. النتائج: تم العثور على النموذج الذي تم إنشاؤه عبر تقنية النمذجة الجزيئية التي تقيس علاقة الهيكل بالنشاط الكمي ثنائية الأبعاد على مجموعة البيانات بدرجة عالية من التنبؤية. حدد الفحص الافتراضي للالتحام الجزيئي الذي تم إجراؤه ، المركبات 25 و 32 و 15 و 21 و 23 التي حصلت على أعلى درجات الإرساء كأفضل نتيجة. يحتوي المركب 25 من بينها على أعلى درجة في الإرساء تبلغ -138.329 كيلو كالوري / مول وإعادة تصنيف درجة -95.449. شوهد أن جميع المركبات التي تم تحديدها لديها نتائج أفضل وأعلى في الإرساء ودرجات إعادة ترتيب من العقار القياسي أزد9291. تم التأكد من أن أفضل مركبات الإصابة هي ذات طبيعة شبيهة بالعقاقير من خلال عدم وجود أكثر من انتهاك واحد لشروط الترشيح المستخدمة في تقييم تشابه الدواء لجزيء صغير. وعرضت ميزات الحركية الدوائية الخاصة بهم متوسط ملامح الحرائك الدوائية. الاستنتاجات: يمكن أن تعمل مركبات الإصابة المذكورة كعوامل علاجية محتملة لسرطان الرئة ذو الخلايا غير الصغيرة بسبب سلامتها وفعاليتها بعد اجتياز التجربة قبل السريرية باستثناء المركب 23 الذي وجد أنه سام. وأيضا، يمكن أن تكون بمثابة نموذج لتصميم عوامل علاجية جديدة لسرطان الرئة ذو الخلايا غير الصغيرة. Abstract: Objectives: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly 2 million diagnoses and a 17% 5-year survival rate. The aim of this study was to use computer-aided techniques to identify potential therapeutic agents for NSCLC. Methods: The two dimensional-quantitative structure–activity relationship (2D-QSAR) modeling was employed on some potential NSCLC therapeutic agents to develop a highly predictive model. Molecular docking-based virtual screening were conducted on the same set of compounds to identify potential hit compounds. The pharmacokinetic features of the best hits were evaluated using SWISSADME and pkCSM online web servers, respectively. Results: The model generated via 2D-QSAR modeling was highly predictive with R2= 0.798, R2adj = 0.754, Q2CV = 0.673, R2 test = 0.531, and cRp2 = 0.627 assessment parameters. Molecular docking-based virtual screening identified compounds 25, 32, 15, 21, and 23 with the highest MolDock scores as the best hits, of which compound 25 had the highest MolDock score of −138.329 kcal/mol. All of the identified hits had higher MolDock scores than the standard drug (osimertinib). The best hit compounds were ascertained to be drug-like in nature following the Lipinski’s rule of five. Also, their ADMET features displayed average pharmacokinetic profiles. Conclusion: After successful preclinical testing, the hit compounds identified in this study may serve as potential NSCLC therapeutic agents due to their safety and efficacy with the exception of compound 23, which was found to be toxic. They can also serve as a template for designing novel NSCLC therapeutic agents.

The emergence of multiresistant bacteria and the shortage of antibacterials in the drug pipeline creates the need to search for novel agents. Evolution drives the optimization of the structure of marine natural products to act as antibacterial agents. Polyketides are a vast and structurally diverse family of compounds that have been isolated from different marine microorganisms. Within the different polyketides, benzophenones, diphenyl ethers, anthraquinones, and xanthones have shown promising antibacterial activity. In this work, a dataset of 246 marine polyketides has been identified. In order to characterize the chemical space occupied by these marine polyketides, molecular descriptors and fingerprints were calculated. Molecular descriptors were analyzed according to the scaffold, and principal component analysis was performed to identify the relationships among the different descriptors. Generally, the identified marine polyketides are unsaturated, water-insoluble compounds. Among the different polyketides, diphenyl ethers tend to be more lipophilic and non-polar than the remaining classes. Molecular fingerprints were used to group the polyketides according to their molecular similarity into clusters. A total of 76 clusters were obtained, with a loose threshold for the Butina clustering algorithm, highlighting the large structural diversity of the marine polyketides. The large structural diversity was also evidenced by the visualization trees map assembled using the tree map (TMAP) unsupervised machine-learning method. The available antibacterial activity data were examined in terms of bacterial strains, and the activity data were used to rank the compounds according to their antibacterial potential. This potential ranking was used to identify the most promising compounds (four compounds) which can inspire the development of new structural analogs with better potency and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. [ABSTRACT FROM AUTHOR]

Abstract Chiral piperidine scaffolds are prevalent as the common cores of a large number of active pharmaceuticals in medical chemistry. This review outlined the diversity of chiral piperidine scaffolds in recently approved drugs, and also covers the scaffolds in leads and drug candidates. The significance of chiral piperidine scaffolds in drug design is also discussed in this article. With the introduction of chiral piperidine scaffolds into small molecules, the exploration of drug-like molecules can be benefitted from the following aspect: (1) modulating the physicochemical properties; (2) enhancing the biological activities and selectivity; (3) improving pharmacokinetic properties; and (4) reducing the cardiac hERG toxicity. Given above, chiral piperidine-based discovery of small molecules will be a promising strategy to enrich our molecules' library to fight against diseases.

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration ( S 0 L L P S ) and crystalline solubility ( S 0 c ) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point ( T m ) equation (CLME) was derived ( l o g 10 S 0 C = l o g 10 S 0 L L P S − 0.0095 T m − 310 for 310 K). The S 0 L L P S values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed log 10 S 0 C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit). [ABSTRACT FROM AUTHOR]

Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5–26). The exception was one derivative displaying an SI (>111–189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13–28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity. [ABSTRACT FROM AUTHOR]

The emergence of multiresistant bacteria and the shortage of antibacterials in the drug pipeline creates the need to search for novel agents. Evolution drives the optimization of the structure of marine natural products to act as antibacterial agents. Polyketides are a vast and structurally diverse family of compounds that have been isolated from different marine microorganisms. Within the different polyketides, benzophenones, diphenyl ethers, anthraquinones, and xanthones have shown promising antibacterial activity. In this work, a dataset of 246 marine polyketides has been identified. In order to characterize the chemical space occupied by these marine polyketides, molecular descriptors and fingerprints were calculated. Molecular descriptors were analyzed according to the scaffold, and principal component analysis was performed to identify the relationships among the different descriptors. Generally, the identified marine polyketides are unsaturated, water-insoluble compounds. Among the different polyketides, diphenyl ethers tend to be more lipophilic and non-polar than the remaining classes. Molecular fingerprints were used to group the polyketides according to their molecular similarity into clusters. A total of 76 clusters were obtained, with a loose threshold for the Butina clustering algorithm, highlighting the large structural diversity of the marine polyketides. The large structural diversity was also evidenced by the visualization trees map assembled using the tree map (TMAP) unsupervised machine-learning method. The available antibacterial activity data were examined in terms of bacterial strains, and the activity data were used to rank the compounds according to their antibacterial potential. This potential ranking was used to identify the most promising compounds (four compounds) which can inspire the development of new structural analogs with better potency and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.

In this paper, density, solubility parameter and transport properties viscosity, thermal conductivity and diffusion coefficient at infinite dilution in water (diffusivity) of drug-like fluids including two groups have been calculated. We have studied the modified perturbed hard trimmer chain equation of state combined with statistical model and modified rough hard-sphere (RHS) theory to model the solubility parameter and transport properties of drug-like fluids for temperature ranging from 129.95 to 1090.15 K and atmosphere pressure. From 838 experimental data points examined, the average absolute relative deviation (AARD) of calculated density was found to be 1.05%. In the case of solubility parameter, the new statistical-based model correlated 234 experimental data points with AARD equal to 0.70%. RHS-based model has also been extended to calculated 601, 771 and 261 experimental data points of viscosity, thermal conductivity and diffusivity with AARD equal to 3.11%, 2.12% and 7.69%, respectively. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS−0.0095Tm−310 for 310 K). The S0LLPS values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at log10S0C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit).

Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5–26). The exception was one derivative displaying an SI (>111–189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13–28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity.

The present work is devoted to the synthesis of imidazo[2,1-b][1,3]thiazine derivatives as possible anti-inflammatory agents. The synthetic approach to (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines based on the interaction of the polysubstituted 2-chloropyridines with 3-hydroxy-imidazo[2,1-b][1,3]thiazines was proposed. Selective nucleophilic substitution in position 2 of a pyridine ring was observed in the mentioned reaction. The synthesized (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines drug-like properties were studied in silico using SwissADME and anti-inflammatory activity in the carrageenan test in vivo. Hit-compounds with satisfactory drug-like and pharmacological features were identified as promising objects for forthcoming structure optimization and in-depth studies.

Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics. [ABSTRACT FROM AUTHOR]

Several hundred (396) compounds from New Zealand flora with medicinal properties were analyzed for their physicochemical properties. It was found that approximately 10 % fulfilled all the requirements to be considered to be lead‐like, over half of the compounds were deemed to be in the drug‐like space and ≈75 % were in the known drug space. These results indicate the presence of a significant proportion of compounds that are of particular interest to pursue as potential lead compounds or therapeutics. Additionally, compound classes were analyzed separately—most carbonyl‐containing compounds (aldehydes, ketones, esters and lactones), along with phenols were the most lead‐like compounds, which also displayed very good proportions in the drug‐like and known drug space. The information presented herein can be harnessed and utilized in future work, through focussing on the compounds and compound classes that exhibit high‐levels of lead‐likeness for further development. [ABSTRACT FROM AUTHOR]

The physicochemical properties of classical lignans, neolignans, flavonolignans and carbohydrate-lignan conjugates (CLCs) were analysed to assess their ADMET profiles and establish if these compounds are lead-like/drug-like and thus have potential to be or act as leads in the development of future therapeutics. It was found that while no studied compounds were lead-like, a very large proportion (>75%) fulfilled all the requirements to be deemed as present in drug-like space and almost all compounds studied were in the known drug space. Principal component analysis was an effective technique that enabled the investigation of the relationship between the studied molecular descriptors and was able to separate the lignans from their sugar derivatives and flavonolignans, primarily according to the parameters that are considered when defining chemical space (i.e., number of hydrogen bond donors, acceptors, rotatable bonds, polar surface area and molecular weight). These results indicate that while CLCs and flavonolignans are less drug-like, lignans show a particularly high level of drug-likeness, an observation that coupled with their potent biological activities, demands future pursuit into their potential for use as therapeutics. [ABSTRACT FROM AUTHOR]

Deep-sea natural products have been created by unique marine organisms that thrive in a challenging environment of extreme conditions for its inhabitants. In this study, 179 deep-sea natural products isolated from 2009 to 2013 were investigated by analysing their physicochemical properties that are important indicators of the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile of a compound. The study and analysis of these molecular descriptors and characteristics enabled the defining of these compounds in various chemical spaces, particularly as an indication of their drug-likeness and position in chemical space and is the first to be conducted to analyse deep-sea derived natural products. It was found that ~40% of all deep-sea natural products were drug-like and 2/3 were within Known Drug Space (KDS), highlighting the high drug-likeness of a significant proportion of deep-sea natural products, most of which have already been shown to have notable biological activities, that should be further investigated as potential therapeutics. Furthermore, this study was able to reveal the general structural differences between compounds from Animalia, Bacteria and Fungi organisms where it was observed that natural products from members of the Animalia kingdom are structurally more varied than compounds from bacteria and fungi. It was also noted that, in general, fungi-derived compounds occupy a more favourable position in drug-like chemical space and are a rich and promising source of biologically-active natural products for the purposes of drug development and therapeutic application.

The physicochemical properties of classical lignans, neolignans, flavonolignans and carbohydrate-lignan conjugates (CLCs) were analysed to assess their ADMET profiles and establish if these compounds are lead-like/drug-like and thus have potential to be or act as leads in the development of future therapeutics. It was found that while no studied compounds were lead-like, a very large proportion (>75%) fulfilled all the requirements to be deemed as present in drug-like space and almost all compounds studied were in the known drug space. Principal component analysis was an effective technique that enabled the investigation of the relationship between the studied molecular descriptors and was able to separate the lignans from their sugar derivatives and flavonolignans, primarily according to the parameters that are considered when defining chemical space (i.e., number of hydrogen bond donors, acceptors, rotatable bonds, polar surface area and molecular weight). These results indicate that while CLCs and flavonolignans are less drug-like, lignans show a particularly high level of drug-likeness, an observation that coupled with their potent biological activities, demands future pursuit into their potential for use as therapeutics.

Background In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e g, new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. Methods The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as 'signposts' in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. Results This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 µM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. Conclusion A selection cascade was applied to prioritize hits resulting from the screening of a mediumsized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested. [ABSTRACT FROM AUTHOR]

Context: Galbanic acid (GA) is a biologically active sesquiterpene coumarin from Ferula species (Apiaceae). This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral, and antileishmanial activities. Objectives: This article is a review on the synthesis, biosynthesis, and biological activities of GA. In addition, we discussed gaps in our knowledge about GA that deserve future research. In this article, we also evaluated the drug-likeness of GA in silico. Methods: All relevant databases were searched for the terms 'galbanic acid', 'methyl galbanate', ' Ferula' and 'sesquiterpene coumarin' without limitation, up to May 2013. Information on GA was collected via electronic search using Pubmed, Scopus, Web of Science, and Sciencedirect. All physicochemical parameters used for the prediction of drug-likeness were calculated using MarvinSketch (version 5.11, academic package, ChemAxon). Results: This compound showed various biological properties including anticancer, cancer chemopreventive, anticoagulant, antiviral and antileishmanial activities. GA can inhibit the growth of prostate cancer cells via decreasing androgen receptor abundance. In silico physicochemical studies on GA showed that this compound has drug-like properties, the parameters that are important to predict potential of a compound for being a future drug. Conclusion: GA is a valuable natural product with various biological activities. New discoveries with GA are to be expected. [ABSTRACT FROM AUTHOR]

Objectives: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly 2 million diagnoses and a 17% 5-year survival rate. The aim of this study was to use computer-aided techniques to identify potential therapeutic agents for NSCLC., Methods: The two dimensional-quantitative structure-activity relationship (2D-QSAR) modeling was employed on some potential NSCLC therapeutic agents to develop a highly predictive model. Molecular docking-based virtual screening were conducted on the same set of compounds to identify potential hit compounds. The pharmacokinetic features of the best hits were evaluated using SWISSADME and pkCSM online web servers, respectively., Results: The model generated via 2D-QSAR modeling was highly predictive with R 2 = 0.798, R 2 adj = 0.754, Q 2 CV = 0.673, R 2 test = 0.531, and cRp 2 = 0.627 assessment parameters. Molecular docking-based virtual screening identified compounds 25, 32, 15, 21, and 23 with the highest MolDock scores as the best hits, of which compound 25 had the highest MolDock score of -138.329 kcal/mol. All of the identified hits had higher MolDock scores than the standard drug (osimertinib). The best hit compounds were ascertained to be drug-like in nature following the Lipinski's rule of five. Also, their ADMET features displayed average pharmacokinetic profiles., Conclusion: After successful preclinical testing, the hit compounds identified in this study may serve as potential NSCLC therapeutic agents due to their safety and efficacy with the exception of compound 23, which was found to be toxic. They can also serve as a template for designing novel NSCLC therapeutic agents., (© 2022 [The Author/The Authors].)

The 3′-ends of human chromosomal DNA terminate in short single-stranded guanine-rich tandem-repeat sequences. In cancer cells, these are associated with the telomere-maintenance enzyme telomerase together with the end-binding protein hPOT1. Small molecules that can compete with these proteins and induce the single-stranded DNA to form quadruplex–ligand complexes are, in effect, able to expose these 3′-ends, which results in the activation of a DNA damage response and selective inhibition of cell growth. Several of these G-quadruplex binding molecules have shown promising anticancer activity in tumour xenograft models, which indicate that the approach may be applicable to the treatment of a wide range of human cancers. This minireview summarizes the available data on these compounds and the challenges posed for drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: Despite the extensive literature describing the role of the ATP-gated P2X3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. [Copyright &y& Elsevier]

Acid-base ionization constant (pKa) values have considerable influence on the physicochemical and pharmacokinetic properties of therapeutic substances. A set of 907 drugs was examined to determine the proportion of drugs that contain an ionizable group and the distribution of their pKa values. Using this contemporary set of compounds it was found that 64% of these compounds contained an ionizable group. Within this group of ionizable compounds, 34% contained a single basic group while only 20% contained a single acidic functional group. The single acid and single base containing substances were investigated further to examine the distributions of their pKa values. These data are discussed and analyzed with a focus on the entire set as well as central nervous system, non-central nervous system and oral drugs. The findings from this research will prompt pharmaceutical companies to assess the constitution of their screening libraries, such that focus is placed on the proportion of ionizable substances, the ratio of acids to bases and the distribution of pKa values. [ABSTRACT FROM AUTHOR]

Abstract: P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X3 and P2X2/3 receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X3/P2X2/3 antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X3/P2X2/3 antagonist. [Copyright &y& Elsevier]