An in-silico scaffold- hopping approach to design novel inhibitors against gp130: A potential therapeutic application in cancer and Covid-19.

An upregulation of the gp130-signalling cascade has been reported in multiple cancers, making gp130 an attractive target for the development of anticancer drugs. An inverted-funnel-like approach was utilised along with various structure-based drug designing strategies to discover and optimise novel potential inhibitors of gp130. The study resulted in the discovery of 2 ligands- 435 and 510, both of which exhibit a very high-binding affinity towards the gp130 D1 domain which controls cytokine recognition and interaction thus being involved in complexation. The two resulting complexes remained stable over time with the ligands maintaining a steady interaction with the target. This inference is drawn from their RMSD, Rg, SASA and RMSF analysis. We also tested the protein folding patterns based on their principal component analysis, energy of surface and landscape. The leads also displayed a more favourable ADMET profile than their parent compounds. The two lead candidates show a better therapeutic profile in comparison to the two existing drugs- bazedoxifene and raloxifene. Both these potential leads can be addressed for their activity in-vitro and can be used as a potential anti-cancer treatment as well as to combat Covid-19 related cytokine storm.

Molecular Design of Novel Inhibitor by Targeting IL-6Rα using Combined Pharmacophore and Experimentally Verified Plant Products with Scaffold-Hopping Techniques: A Dual Therapeutic Strategy for COVID-19 and Cancer.

The IL-6/IL-6R/gp130 complex serves as a significant indicator of cytokine release syndrome in COVID-19 and chronic inflammation, increasing the risk of cancer. Therefore, we identified IL-6Rα as a potential target to block gp130 interaction. Notably, there has been no reception of approval for an orally available drug to serve this purpose, to date. In this study, we targeted IL-6Rα to inhibit IL-6Rα/gp130 interaction. The selection of the lead candidate L821 involved the amalgamation of three drug discovery approaches. This library was screened employing tertiary structure-based pharmacophore models followed by molecular docking models, scaffold-hopping, MM/PBSA as well as MM/GBSA analysis, and assessments of pKi and ADMET properties. After evaluating the binding interactions with key amino acids, 15 potential ligands were chosen, with the top ligand undergoing further investigation by means of molecular dynamics simulations. Considering the stability of the complexes, the strong interactions observed between ligand and residues of IL-6Rα/gp130, and the favorable binding free energy calculations, L821 emerged as the prime candidate for inhibiting IL-6Rα. Notably, L821 exhibited a docking-based binding affinity of -9.5 kcal/mol. Our study presents L821 as a promising inhibitor for future in vitro analysis, potentially combatting SARS-CoV-2-related cytokine storms and serving as an oncogenic drug therapy.

An in-silico receptor-pharmacophore based multistep molecular docking and simulation study to evaluate the inhibitory potentials against NS1 of DENV-2.

DENV-2 strain is the most fatal and infectious of the five dengue virus serotypes. The non-structural protein NS1 encoded by its genome is the most significant protein required for viral pathogenesis and replication inside the host body. Thus, targeting the NS1 protein and designing an inhibitor to limit its stability and secretion is a propitious attempt in our fight against dengue. Four novel inhibitors are designed to target the conserved cysteine residues (C55, C313, C316, and C329) and glycosylation sites (N130 and N207) of the NS1 protein in an attempt to halt the spread of the dengue infection in the host body altogether. Numerous computer-aided drug designing techniques including molecular docking, molecular dynamics simulation, virtual screening, principal component analysis, and dynamic cross-correlation matrix were employed to determine the structural and functional activity of the NS1-inhibitor complexes. From our analysis, it was evident that the extent of structural and atomic level fluctuations of the ligand-bound protein exhibited a declining trend in contrast to unbound protein which was prominently noticeable through the RMSD, RMSF, Rg, and SASA graphs. The ADMET analysis of the four ligands revealed a promising pharmacokinetics and pharmacodynamic profile, along with good bioavailability and toxicity properties. The proposed drugs when bound to the targeted cavities resulted in stable conformations in comparison to their unbound state, implying they have good affinity promising effective drug action. Thus, they can be tested in vitro and used as potential anti-dengue drugs.Communicated by Ramaswamy H. Sarma.

Design and development of novel potential inhibitors of the human USP21 enzyme using a pharmacophore-based virtual screening technique.

An overexpression and increase have been observed in the concentration and activity of the ubiquitin-specific protease 21 (USP21) enzyme in many cancers, necessitating the need for the development of new inhibitor drugs against the same. The current study attempts to discover one such novel potential inhibitor of USP21 by the application of various bioinformatics techniques which include molecular modeling, pharmacophore mapping, pharmacophore-based virtual screening, molecular docking, and ADMET prediction followed by molecular dynamics simulations. Following this inverted funnel-like approach, we finally ended up with one ligand-ZINC02422616 which displays a very high binding affinity toward the USP21 domain. This ligand contains all the pharmacophoric features displayed by the compounds that are potential inhibitors of the USP21 domain. Moreover, it shows a favorable pharmacokinetic, pharmacodynamic, and ADMET profile, along with strong hydrophobic interaction and hydrogen bonding with the domain. Simulation studies showed that the complex remains stable over time, with the bound protein displaying a more constrained motion in the conformational space compared to the unbound form. The ligand showed a highly favorable free energy landscape/surface, forming several energy minima's in contrast to the unbound domain in which most conformations occupied a relatively higher energy state. Moreover, the ligand also displayed a Kd of 422.8 nM and a free energy of binding ΔG of -8.6 kcal/mol, both of which indicate a very high affinity toward the target domain. This potential drug candidate can then be used as a viable treatment method for many types of cancers caused by USP21.