Exploring Cytotoxic Potential of Ciclopirox on Colorectal Cancer Cells by In-Silico Methodology

Colorectal cancer (CRC) stands 3rd among male cancer cases and the second most prevalent disease in women, accounting for 10% of all cancer cases globally. Ciclopirox (CPX) is a broad-spectrum, synthetic, off-patent antifungal drug recommended in dermatological conditions of mycoses of the skin and nails. There are no important molecular docking studies on inhibitory aspects of CPX against CRC targets. The main objective of this study was to explore the potential of CPX as an anti-CRC agent by using in-silico approaches with the help of published literature on downregulation of overhead protein expression in CRC and combining this information in order to recognize novel drug targets [Cell division cycle 25A (Cdc25A), Protein deglycase DJ-1 (DJ-1), Retinoblastoma protein (p-Rb/Rb), Cyclin-dependent kinase-4 (CDK4), High-mobility group AT-hook-2 (HMGA2), and Catenin β-1 (Wnt/-catenin)] and to identify the perspectives for drug repurposing and comparing this with oxaliplatin; one of the standard drug used in CRC. Also, in silico drug-likeliness studies, bioavailability studies, pharmacokinetic studies, drug target prediction, and bioisosteric replacement have been performed for CPX using online SwissADME tools (SwissADME, SwissTargetPrediction, and SwissBioisostere). The in silico studies revealed that CPX successfully inhibited all the molecular targets, which suggested plausible re-utilization of CPX for treating CRC.

Identification of Isosteric Replacements of Glycosyl Domain of Ligands by Data Mining

Biologically equivalent replacements of key moieties in molecule rationalizes scaffold hopping, patent busting or R-group enumeration, yet heavily depending upon the expert-defined space therefore is subjective and might be biased to the chemistries they get used to. Most importantly, these explorations are often informatively incomplete since it is often confined within try-and-error cycle, only meaning what kind of substructures are suitable for the replacement occur, but fail to disclose the driving forces to support such interchanges. The Protein Data Bank (PDB) repository involving receptor-ligand interactional information reminds poorly exploited. However, manual screening the PDB become almost impossible to excavate the bioisosteric know-how with the exponentially increase of data. Therefore, a textual content parsing workflow is developed to automatedly mine local structural replacement (LSR) of specific structure. Taking the glycosyl domain for instance, a total of 41652 replacements that overlap on nucleotide ribose were identified and categorized based on their SMILE codes. Predominately ring system, such as aliphatic aromatic ring, yet amide and sulfonamide replacement also occurred. We believe these findings may enlighten medicinal chemists to design and optimize ligand structure using bioisosteric replacement strategy.

New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.

Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ1 receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the “left” five-membered ring and various amino groups on the “right” side; (2) benzylamino or analogous amino moieties on the “right” side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ1 affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ1 affinity (Ki = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the “left” hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ1 affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ1 affinity of 9a (Ki = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ1 receptor, which result in energetic values correlating well with their different σ1 affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ1 receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ1 receptor-binding pocket, which explains the higher σ1 affinity of the unsubstituted azapropellane 9a.

Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replacement. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety.