New dynamic scoring method for deep evaluation of naloxegol as ß-tubulin binding inhibitor.

We report a new scoring method for rating the performance of ligands on same protein, using their extensive dynamic flexibility properties, binding with protein and impact on receptor protein. Based on molecular dynamics (MD), this method is more accurate than single-point energy calculations. This method identified an ideal FDA-approved drug as ß-tubulin microtubule inhibitor with improved attributes compared to commercial microtubule disassembly inhibitor, Paclitaxel (PTX). We started with virtual screening (VS) of FDA-approved drugs inside PTX's binding pocket (A) of human ß-tubulin protein. Screened ligands (>80% score) were evaluated for non-permeation through blood-brain barrier (BBB) as targets were body cancers, gastrointestinal absorption, Lipinski, non-efflux from central nervous system (CNS) by p-glycoprotein (Pgp), and ADMET analysis. This identified FDA-approved Naloxegol drug with superior attributes compared to PTX. Pocket (A) specific docking of chain length variable derivatives of Naloxegol gave docked poses that underwent MD run to give a range of properties and their descriptors (RMSD, RMSF, RoG, H-bonds, hydrophobic interaction and SASA). QSPR validated that MD properties dependent upon [-CH2-CH2-O-]n=0-7 chain length of Naloxegol. MD data underwent normalization, PCA analysis and scoring against PTX. One Naloxegol derivative scored higher than PTX as a potential microtubule disassembly inhibitor.

Advancements in steroidal Pt(II) & Pt(IV) derivatives for targeted chemotherapy (2000-2023).

One of the key strategies in chemotherapy involves crosslinking the DNA strands of cancer cells to impede their replication, with platinum (Pt) coordination compounds being a prominent class and cisplatin being its major representative. Steroidal ligands tethered to DNA interactive Pt core act as drug carriers for targeted therapy. While crosslinking of nuclear or mitochondrial DNA strands using coordination complexes has been studied for years, there remains a lack of comprehensive reviews addressing the advancements made in steroidal-Pt derivatives. This review specifically focuses on advancements made in steroid-tethered structural derivatives of Pt(II) or prodrug Pt(IV) for targeted chemotherapy, synthesized between 2000 and 2023. This period was deliberately chosen due to the widespread use of computational techniques for more accurate structure-based drug-design in last two decades. This review discusses the strategy behind tethering steroidal ligands such as testosterone, estrogen, bile acids, and cholesterol to the central DNA interactive Pt core through specific linker groups. The steroidal ligands function as drug delivery vehicles of DNA interactive Pt core and bind with their respective target receptors or proteins that are often overexpressed in cancer cells, thus enabling targeted delivery of Pt moiety to interact with DNA. We discussed structural features such as the location of the linker group on the steroid, the mono, bi, and tridentate configuration of the chelating arm in coordination with Pt, and the rigidity and flexibility of the linker group. The comparative in vitro, in vivo activities, and relative binding affinities of the designed compounds against standard Pt drugs are also discussed. We also provided a critique of observed trends and shortcomings. Our review will provide insights into future molecular designing of targeted DNA crosslinkers and their structural optimization to achieve desired drug properties. From this analysis, we proposed further research directions leading to the future of targeted chemotherapy.

Colorimetric chromophoric rapid detection of SARS-CoV-2 through breath analysis.

Early and rapid detection of SARS-CoV-2 in an infected person is one fundamental part of the strategy against the spread of this virus. As of now, the usual practice is to carry out polymerase chain reaction (PCR) test which provides results in 24-48 hours. Hence, there exists a crucial need for rapid and immediate screening of people suspected to be infected. Presence of volatile organic compounds (VOCs) in the exhaled breath can be one such prospect for detection of virus. In this paper, we have designed chromophoric adducts of VOC's in the exhaled breath that can be formed for colorimetric detection of SARS-CoV-2. We noted the bathochromic shift in λ (nm) of VOC molecules upon chromophore formation for colorimetric detection. If adapted, this research work will result in low cost solution to the requirement of immediate detection of SARS-CoV-2, hence cost and time of testing will be reduced, compared to PCR and antibodies tests. Also VOC's detection in early stage of infection where symptoms are not visible can be advantageous.

Docking analysis of aryl derivatives of diepoxide alkylating agents.

In this research, molecular structural manipulation of treosulfan alkylating agent and resultant changes in binding is studied to assist in designing derivatives of treosulfan for synthesis. Molecular docking has been conducted on simulated heterocyclic polyaromatic alkylating diepoxide derivatives of treosulfan with DNA nucleobases of dodecamer duplex of sequences d(CGCGAATTCGCG) and d(CGCGAATTCGCG) using Autodock vina package. Two series of simulated diepoxide molecules were designed with increasing aryl ring chain in linear and fused aryl way between the two epoxide reactive rings. Relationship between increasing no. of aryl rings (both linear and fused) between epoxide moieties on the binding energy values was evaluated. We also identified that designed molecules bind specifically to Guanine and Cytosine (GC) base pairs on DNA. Mode of interaction and resultant behavior as an alkylating agent or as minor groove binder was also found to be dependent up on the no. of aryl rings and their connectivity in the molecule. Both linearly bonded and fused aryl rings in higher number, between the epoxide rings, gave the strongest binding with the binding energy up to -8.1 and -8.7 Kcal/mol, respectively. These relationships can immensely help in designing and synthesis of derivatives of treosulfan like diepoxide based alkylating agents.

Derivatives of diisopropyl phenoxyphosphate with controlled reactivity for enhancement of Acetylcholine (ACh) neurotransmitter.

Here, new phenoxide derivatives of diisopropyl flourophosphate for reaction with Lewis basic sites on acetyl cholinesterase (AChE) were designed. Such binding interaction or reaction inhibits the hydrolysis of the acetylcholine (ACh) neurotransmitter thus enhancing its concentration. This increased neurotransmitter concentration can enhance memory and cognition thus improving symptoms of neurodegenerative diseases such as Alzheimer disease and down syndrome. For docking analysis, we particularly targeted those reception sites on AChE that interacts with the ACh. This led to structural design of derivatives of diisopropyl phenoxyphosphate with controlled reactivity stemming from para substituted phenoxide leaving group. Impact of electron donating (CH3, OCH3) and withdrawing substituents (COCH3) on para position of phenol group on rate of acyl addition elimination reaction was modeled using QM DFT technique. Difference in activation energy between electron donating and withdrawing substituents on phenoxide was noted hence making the derivatives of diisopropyl phenoxyphosphate less reactive and more selective. Docking also confirmed binding of designed derivatives with AChE. Hence novel derivatives with high binding energy and controlled reactivity were designed for retrosynthesis.

Aryl sulfonate based anticancer alkylating agents.

This research work revolves around synthesis of antineoplastic alkylating sulfonate esters with dual alkylating sites for crosslinking of the DNA strands. These molecules were evaluated as potential antineoplastic cross linking alkylating agents by reaction with the nucleoside of Guanine DNA nucleobase at both ends of the synthesized molecule. Synthesis of the alkylating molecules and the crosslinking with the guanosine nucleoside was monitored by MALDITOF mass spectroscopy. The synthesized molecule's crosslinking or adduct forming rate with the nucleoside was compared with that of 1,4 butane disulfonate (busulfan), in form of time taken for the appearance of [M+H]+. It was found that aryl sulfonate leaving group was causing higher rate of nucleophilic attack by the Lewis basic site of the nucleobase. Furthermore, the rate was also found to be a function of electron withdrawing or donating nature of the substituent on the aryl ring. Compound with strong electron withdrawing substituent on the para position of the ring reacted fastest. Hence, new alkylating agents were synthesized with optimized or desired reactivity.