Dual Anti-Inflammatory and Anticancer Activity of Novel 1,5-Diaryl Pyrazole Derivatives: Molecular Modeling, Synthesis, In Vitro Activity, and Dynamics Study.

A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC50) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC50 of 4.655µM and T5 with IC50 of 5.596 µM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.

Identification of novel CA IX inhibitor: Pharmacophore modeling, docking, DFT, and dynamic simulation.

Human Carbonic anhydrase IX (hCA IX) is found to be an essential biomarker for the treatment of hypoxic tumors in both the early and metastatic stages of cancer. Due to its active function in maintaining pH levels and overexpression in hypoxic conditions, hCA IX inhibitors can be a potential candidate specifically designed to target cancer development at various stages. In search of selective hCA IX inhibitors, we developed a pharmacophore model from the existing natural product inhibitors with IC50 values less than 50 nm. The identified hit molecules were then investigated on protein-ligand interactions using molecular docking experiments followed by molecular dynamics simulations. Among the zinc database 186 hits with an RMSD value less than 1 were obtained, indicating good contact with key residues HIS94, HIS96, HIS119, THR199, and ZN301 required for optimum activity. The top three compounds were subjected to molecular dynamics simulations for 100 ns to know the protein-ligand complex stability. Based on the obtained MD simulation results, binding free energies are calculated. Density Functional Theory (DFT) studies confirmed the energy variation between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). The current study has led to the discovery of lead compounds that show considerable promise as hCA IX inhibitors and suggests that three compounds with special molecular features are more likely to be better-inhibiting hCA IX. Compound S35, characterized by a higher stability margin and a smaller energy gap in quantum studies, is an ideal candidate for selective inhibition of CA IX.

Ligand based pharmacophore modelling and integrated computational approaches in the quest for small molecule inhibitors against hCA IX.

Carbonic anhydrase IX is an important biomarker to fight hypoxic tumours in both initial and metastatic stages of many forms of cancer. Overexpression of hCA IX in the hypoxic environment, has an active role in pH maintenance and makes the hCA IX a better target for the inhibitors targeting specific types of cancer stages. Being a member of the carbonic anhydrase family and having sixteen isoforms, it is important to have a selective inhibition of hCA IX to limit the disruption in the biological and metabolic pathways where other isoforms of hCA are localised and to avoid the other toxicity and adverse effects we try to find selective hCA IX inhibitors from a natural derivative. In the process of finding selective hCA inhibitors we developed a pharmacophore model based on existing inhibitors with IC50 values of less than 50 nm, which is then validated with the external decoy set and used for database searching followed by virtual screening to identify the hits based on the pharmacophore fit score and RMSD. Molecular docking studies were performed to identify protein ligand interaction and molecular dynamics simulation studies to analyse the stability of the complex and DFT studies were carried out. The initial screening yielded 43 hits with the RMSD value less than 1, which when subjected to docking exhibited very good interaction with key residues ZN301, HIS94, HIS96 and HIS119. The top 4 compounds in the molecular dynamics simulation studies for 100 ns provided useful insights on the stability of the complex and the DFT studies confirmed the energy variation between HOMO and LUMO is within an acceptable range. An average binding score of -7.8 Kcal mol-1 for the lead compounds and high stability margin in the dynamics study concludes that these lead compounds demonstrated outstanding potential for hCA IX inhibitory action theoretically and that further experimental studies for selective inhibition are inevitable.

Discovery and development of COVID-19 vaccine from laboratory to clinic.

The world has recently experienced one of the biggest and most severe public health disasters with severe acute respiratory syndrome coronavirus (SARS-CoV-2). SARS-CoV-2 is responsible for the coronavirus disease of 2019 (COVID-19) which is one of the most widespread and powerful infections affecting human lungs. Current figures show that the epidemic had reached 216 nations, where it had killed about 6,438,926 individuals and infected 590,405,710. WHO proclaimed the outbreak of the Ebola virus disease (EVD), in 2014 that killed hundreds of people in West Africa. The development of vaccines for SARS-CoV-2 becomes more difficult due to the viral mutation in its non-structural proteins (NSPs) especially NSP2 and NSP3, S protein, and RNA-dependent RNA polymerase (RdRp). Continuous monitoring of SARS-CoV-2, dynamics of the genomic sequence, and spike protein mutations are very important for the successful development of vaccines with good efficacy. Hence, the vaccine development for SARS-CoV-2 faces specific challenges starting from viral mutation. The requirement of long-term immunity development, safety, efficacy, stability, vaccine allocation, distribution, and finally, its cost is discussed in detail. Currently, 169 vaccines are in the clinical development stage, while 198 vaccines are in the preclinical development stage. The majority of these vaccines belong to the Ps-Protein subunit type which has 54, and the minor BacAg-SPV (Bacterial antigen-spore expression vector) type, at least 1 vaccination. The use of computational methods and models for vaccine development has revolutionized the traditional methods of vaccine development. Further, this updated review highlights the upcoming vaccine development strategies in response to the current pandemic and post-pandemic era, in the field of vaccine development.

Exploring cyclin-dependent kinase inhibitors: a comprehensive study in search of CDK-6 inhibitors using a pharmacophore modelling and dynamics approach.

Cancer prevalence and resistance issues in cancer treatment are a significant public health concern globally. Among the existing strategies in cancer therapy, targeting cyclin-dependent kinases (CDKs), especially CDK-6 is found to be one of the most promising targets, as this enzyme plays a pivotal role in cell cycle stages and cell proliferation. Cell proliferation is the characteristic feature of cancer giving rise to solid tumours. Our research focuses on creating novel compounds, specifically, pyrazolopyrimidine fused azetidinones, using a groundbreaking molecular hybridization approach to target CDK-6. Through computational investigations, ligand-based pharmacophore modelling, pharmacokinetic studies (ADMET), molecular docking, and dynamics simulations, we identified 18 promising compounds. The pharmacophore model featured one aromatic hydrophobic centre (F1: Aro/Hyd) and two H-bond acceptors (F2 and F3: Acc). Molecular docking results showed favourable binding energies (-6.5 to -8.0 kcal mol-1) and effective hydrogen bonds and hydrophobic interactions. The designed compounds demonstrated good ADMET profiles. Specifically, B6 and B18 showed low energy conformation (-7.8 kcal and -7.6 kcal), providing insights into target inhibition compared to the standard drug Palbociclib. Extensive molecular dynamics simulations confirmed the stability of these derivatives. Throughout the 100 ns simulation, the ligand-protein complexes maintained structural stability, with acceptable RMSD values. These compounds hold promise as potential leads in cancer therapy.

An overview of mechanism and chemical inhibitors of shikimate kinase.

Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs because of genetic alterations, and the molecular insights suggest that the accumulation of mutation in the individual drug target genes is the primary mechanism of multi-drug resistant tuberculosis. Chorismate is an essential structural fragment for the synthesis of aromatic amino acids and synthesized biochemically by a number of bacteria, including Mycobacterium tuberculosis, utilizing the shikimate pathway. This shikimate kinase is the newer possible target for the generation of novel antitubercular drug because this pathway is expressed only in mycobacterium and not in Mammals. The discovery and development of shikimate kinase inhibitors provide an opportunity for the development of novel selective medications. Multiple shikimate kinase inhibitors have been identified via insilico virtual screening and related protein-ligand interactions along with their in-vitro studies. These inhibitors bind to the active site in a similar fashion to shikimate. In the current review, we present an overview of the biology and chemistry of the shikimate kinase protein and its inhibitors, with special emphasis on the various active scaffold against the enzyme. A variety of chemically diversified synthetic scaffolds including Benzothiazoles, Oxadiazoles, Thiobarbiturates, Naphthoquinones, Thiazoleacetonitriles, Hybridized Pyrazolone derivatives, Orthologous biological macromolecule derivatives, Manzamine Alkaloids derivatives, Dipeptide inhibitor, and Chalcones are discussed in detail. These derivatives bind to the specific target appropriately proving their potential ability through different binding interactions and effectively explored as an effective and selective Sk inhibitor.Communicated by Ramaswamy H. Sarma.