IN SILICO STUDIES OF (S)-2-AMINO-4-(3,5-DICHLOROPHENYL) BUTANOIC ACID AGAINST LAT1 AS A RADIOTHERANOSTIC AGENT OF CANCER

Objective: This study aims to obtain a good activity of radiotheranostic kit for cancer which is built by combining (S)-2-amino-4-(3,5-dichlorophenyl) butanoic acid (ADPB) with various bifunctional chelators. Methods: This study was conducted through in silico method that consists of molecular docking simulation using AutoDock 4 as well as ADMET prediction using vNN-ADMET and Pre-ADMET. Six bifunctional chelators (i.e. CTPA, DOTA, H2CB-TE2A, H2CB-DO2A, NOTA, and TETA) were conjugated with ADPB as a carrier molecule and further analyzed through molecular docking and ADMET prediction. Results: The results showed that the ADPB-NOTA has the best affinity with the Gibbs free energy (ΔG) of-7.68 kcal/mol with an inhibition constant of 2.36 µM and its ability to bind with the gating residue of LAT1 (ASN258) through hydrogen interactions. Besides that, the ADPB-NOTA compound has a good ADME profile and is predicted to be safe for human use. Conclusion: This study showed that ADPB-NOTA is the most prospective candidate to be used as a radiotheranostic agent.

Molecular Modeling Study for the Evaluation of Natural Compounds as Potential Lanosterol 14α-demethylase Inhibitors

Background: Candida albicans is one of the most important causes of fatal fungal infections. Ergosterol, the main sterol in the fungal cell membrane, is the resultant product of Lanosterol in the presence of the enzyme Lanosterolα-demethylase (Cytochrome P450DM). This enzyme is the target enzyme of azole antifungal agents. Aim: To evaluate the antifungal potency of some of the natural compounds via molecular modeling and Absorption, Distribution, Metabolism and Excretion (ADME) study. Method: The study involved the selection and modeling of the target enzyme, followed by the refinement of the model using molecular dynamic simulation. The modelled structure of the enzyme was validated using the Ramachandran plot and Sequence determination technique. A series of natural compounds was evaluated for cytochrome P450 inhibitory activity using molecular docking studies. The structures of compounds were prepared using a Chem sketch, and molecular docking was performed using Molergo Virtual Docker (MVD) program. Results: The docking study indicated that all the natural compounds have interactivity with protein residue of 14α-demethylase, and the heme prosthetic group and water molecules are present at the active site. The data were also correlated with the synthetic compounds that were experimentally inactive against the fungus and had a low docking score. The compounds with a high dock score were further screened for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile, and it was predicted that these compounds can be used as lead with a good ADME profile and low toxicity. Conclusion: The natural compound, i.e., curcumin, can easily be used further for lead optimization.

MetaClass, a Comprehensive Classification System for Predicting the Occurrence of Metabolic Reactions Based on the MetaQSAR Database

(1) Background: Machine learning algorithms are finding fruitful applications in predicting the ADME profile of new molecules, with a particular focus on metabolism predictions. However, the development of comprehensive metabolism predictors is hampered by the lack of highly accurate metabolic resources. Hence, we recently proposed a manually curated metabolic database (MetaQSAR), the level of accuracy of which is well suited to the development of predictive models. (2) Methods: MetaQSAR was used to extract datasets to predict the metabolic reactions subdivided into major classes, classes and subclasses. The collected datasets comprised a total of 3788 first-generation metabolic reactions. Predictive models were developed by using standard random forest algorithms and sets of physicochemical, stereo-electronic and constitutional descriptors. (3) Results: The developed models showed satisfactory performance, especially for hydrolyses and conjugations, while redox reactions were predicted with greater difficulty, which was reasonable as they depend on many complex features that are not properly encoded by the included descriptors. (4) Conclusions: The generated models allowed a precise comparison of the propensity of each metabolic reaction to be predicted and the factors affecting their predictability were discussed in detail. Overall, the study led to the development of a freely downloadable global predictor, MetaClass, which correctly predicts 80% of the reported reactions, as assessed by an explorative validation analysis on an external dataset, with an overall MCC = 0.44.

In silico study and virtual Drug Screening of the FDA-approved approach with Molecular Docking.

Aims: Coronavirus disease 2019 (COVID-19) has emerged in Wuhan, China, and because of fast transmission, it has led to its extensive prevalence in almost all countries, which has made it a global crisis. This study aims to recognize a possible small molecule as a main protease inhibitor versus the main protease protein of SARS-CoV-2 by the computational program.Methods: Virtual screening procedures like using molegro virtual docker, auto dock tools, and auto dock Vina, was done for more than 1600 FDA-approved medicines that download from the ZINC database, were employed to characterize new implied molecule inhibitors for the recently published crystal structure of the main protease protein of SARS-CoV-2. Result: The result indicates that Velpatasvir, angiotensin receptor blockers, cephalosporins, and also atorvastatin could fit adequately to the binding site of the main protease. Because of some other beneficial features, including anti-infectious, anti-inflammatory properties, and ADME profile, they might be a promising drug nominee for repurposing to the treatment of COVID-19.Discussion: Velpatasvir was selected by combining some virtual screening methods for furthers studies to find a suitable ligand for the treatment of COVID-19.

Synthesis of Spiro[cycloalkane-pyridazinones] with High Fsp3 Character

Background: owadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate. Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character. Methods: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study. Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character. Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.

Preclinical evaluation of CLX-155, a novel prodrug of 5-FU for the treatment of cancer.

e15614 Background: CLX-155 is a novel prodrug of 5-FU, developed by adding two acetyl groups (ester bond) and a caprylic acid moiety (amide bond) to 5'-DFCR ring structure. CLX-155 is designed to have a differentiated ADME profile, with improved safety and efficacy over capecitabine. Here, we present the preclinical data of CLX-155 in comparison with capecitabine. Methods: Solubility/stability of CLX-155 was studied in buffers, simulated gastrointestinal fluids and liver microsomes. In vitro metabolite profiling in hepatocytes was done following standard protocol. An oral (gavage) dose range finding (DRF) toxicity, comparative oral pharmacokinetic study and antitumor activity in HCT-116 human colon cancer cell xenograft model was conducted in mice. DRF study in mice evaluated the toxicity of CLX-155 when administered at once daily doses of 100 to 1000 mg/kg/day for 7-days. The oral pharmacokinetics CLX-155/metabolites (5'-DFCR, 5'-DFUR and 5-FU) was determined in mice at MTD dose of 500 mg/kg and for capecitabine at 1000 mg/kg. Antitumor activity of CLX-155 was evaluated in Foxn1 athymic mice at 125, 250 and 500 mg/kg/day and for capecitabine at 1000 mg/kg/day. Treatment was performed for three consecutive weeks (5 days on; 2 days off per week). Results: The results of in-vitro studies confirmed an acceptable profile for further development of CLX-155. Maximum tolerated dose of CLX-155 in mice was 500 mg/kg/day. The key toxicity findings were consistent with the mechanism of action and comparable with capecitabine. Oral PK study in mice showed a lower plasma Cmax for 5'-DFCR, 5'-DFUR and 5-FU. Plasma AUCs of the metabolites were close to or higher than that of capecitabine, indicating an extended absorption or altered metabolism in comparison with capecitabine. CLX-155 caused significant, tumor growth inhibition at all the dose levels tested. Complete tumor regression was seen in 2/10 animals at 500 mg/kg/day of CLX-155. CLX-155 was better tolerated in the mouse xenograft study, no mortality in CLX-155 versus 2/10 in capecitabine group. Conclusions: CLX-155 has an excellent safety and a differentiated ADME profile in relation to capecitabine. This translated into an improved in-vivo antitumor activity for CLX-155 in the HCT 116 xenograft model in relation to capecitabine. Overall data indicate that CLX-155 could offer significant improvements over the currently approved capecitabine in terms of dose size, frequency of administration, safety and interpatient variability in pharmacokinetics.