A hypothesis on designing strategy of effective RdRp inhibitors for the treatment of SARS-CoV-2.

Vaccines are used as one of the major weapons for the eradication of pandemic. However, the rise of different variants of the SARS-CoV-2 virus is creating doubts regarding the end of the pandemic. Hence, there is an urgent need to develop more drug candidates which can be useful for the treatment of COVID-19. In the present research for the scientific hypothesis, emphasis was given on the direct antiviral therapy available for the treatment of COVID-19. In lieu of this, the available molecular targets which include Severe Acute Respiratory Syndrome Chymotrypsin-like Protease (SARS-3CLpro), Papain-Like Cysteine Protease (PLpro), and RNA-Dependent RNA Polymerase (RdRp) were explored. As per the current scientific reports and literature, among all the available molecular targets, RNA-Dependent RNA Polymerase (RdRp) was found to be a crucial molecular target for the treatment of COVID-19. Most of the inhibitors which are reported against this target consisted of the free amine group and carbonyl group which might be playing an important role in the binding interaction with the RdRp protein. Among all the reported RdRp inhibitors, remdesivir, favipiravir, and molnupiravir were found to be the most promising drugs against COVID-19. Overall, the structural features of this RNA-Dependent RNA Polymerase (RdRp) inhibitors proved the importance of pyrrolo-triazine and pyrimidine scaffolds. Previous computational models of these drug molecules indicated that substitution with the polar functional group, hydrogen bond donor, and electronegative atoms on these scaffolds may increase the activity against the RdRp protein. Hence, in line with the proposed hypothesis, in the present research work for the evaluation of the hypothesis, new molecules were designed from the pyrrolo-triazine and pyrimidine scaffolds. Further, molecular docking and MD simulation studies were performed with these designed molecules. All these designed molecules (DM-1, DM-2, and DM-3) showed the results as per the proposed hypothesis. Among all the designed molecules, DM-1 showed promising results against the RdRp protein of SARS-CoV-2. In the future, these structural features can be used for the development of new RdRp inhibitors with improved activity. Also, in the future lead compound DM-1 can be explored against the RdRp protein for the treatment of COVID-19.

Tetrahydroquinoline: an efficient scaffold as mTOR inhibitor for the treatment of lung cancer.

Efforts have been made to find an efficient scaffold (and its substitution) that can be used for the treatment of lung cancer via mTOR inhibition. A detailed literature search was carried out for previously reported mTOR inhibitors. The present review is focused on lung cancer; therefore, descriptions of some mTOR inhibitors that are currently in clinical trials for the treatment of lung cancer are provided. Based on previous research findings, tetrahydroquinoline was found to be the most efficient scaffold to be explored for the treatment of lung cancer. A possible efficient substitution of the tetrahydroquinoline scaffold could also be beneficial for the treatment of lung cancer.

Recent updates on Wnt signaling modulators: a patent review (2014-2020).

Introduction: Wnt signaling is a signal transduction pathway that plays a vital role in embryonic development and normal tissue preservation. Dysfunction of it gives rise to various diseases like cancer, Alzheimer's, metabolic and skeletal disorders, kidney and liver disease, etc. Thus, targeting Wnt pathway can be a potential approach to design and develop novel therapeutic classes.Areas covered: Authors provided an overview of Wnt modulators from 2014 to 2020. Different heterocyclic scaffolds and their pharmacology from a total of 104 PCT applications have been summarized.Expert opinion: The scientific community is working extensively to bring first in the class molecule to the market which targets Wnt pathway. Lorecivivint, Wnt inhibitor, for the treatment of knee Osteoarthritis and SM-04554, Wnt activator, for the treatment of androgenetic alopecia are currently under Phase III. Other molecules, LGK-974, RXC-004, ETC-159, CGX-1321, PRI-724, CWP-232291 and BC-2059 are also under different stages of clinical development for the treatment of cancer. Antibody based Wnt modulator, OTSA101-DTPA-90Y is currently under Phase I for the treatment of Relapsed or Refractory Synovial Sarcoma while OMP-18R5 is under Phase I for Metastatic Breast Cancer.  Ongoing preclinical/clinical trials will define the role of the Wnt pathway in different therapeutic areas and open new opportunities.

Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update.

Poly (ADP-ribose) Polymerase1 (PARP1) is a member of 17 membered PARP family having diversified biological functions such as synthetic lethality, DNA repair, apoptosis, necrosis, histone binding etc. It is primarily a chromatin-bound nuclear enzyme that gets activated by DNA damage. It binds to DNA signal- and double-strand breaks, does parylation of target proteins (using NAD+ as a substrate) like histones and other DNA repair proteins and modifies them as a part of DNA repair mechanism. Inhibition of PARP1 prevents the DNA repair and leads to cell death. Clinically, PARP1 Inhibitors have shown their potential in treating BRCAm breast and ovarian cancers and trials are going on for the treatment of other solid tumors like pancreatic, prostate, colorectal etc. as a single agent or in combination. There are currently three FDA approved PARP1 inhibitors namely Olaparib, Rucaparib and Niraparib in the market while Veliparib and Talazoparib are in the late stage of clinical development. All these molecules are nonselective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency. In addition, resistance to marketed PARP1 inhibitors has been reported. Overall, looking at the success rate of PARP1 inhibitors into various solid tumors, there is an urge of a novel and selective PARP1 inhibitors. This review provides an update on various newer heterocyclic PARP1 inhibitors reported in last three years along with their structural design strategies. We classified them into two main chemical classes; NAD analogues and non-NAD analogues and discussed the medicinal chemistry approaches of each class. To understand the structural features required for in-silico designing of next-generation PARP1 inhibitors, we also reported the crucial amino acid interactions of these inhibitors at the target site. Thus, present review provides the insight on recent development on new lead structures as PARP1 inhibitors, their SAR, an overview of in-vitro and in-vivo screening methods, current challenges and opinion on future designing of more selective and safe PARP1 inhibitors.

Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity.

Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q2) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis.

Design, synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors.

Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model. From this, best 25 derivatives were docked onto the active site of DPP-4 enzyme and in silico ADMET properties were also predicted. Finally, top 17 derivatives were synthesized and characterized using FT-IR, Mass, 1H NMR and 13C NMR spectroscopy. Purity of compounds was checked using HPLC. These derivatives were then evaluated for in vitro DPP-4 inhibition. The most promising compound 15q showed 28.05µM DPP-4 IC50 with 8-10-fold selectivity over DPP-8 and DPP-9 so selected for further in vivo anti-diabetic evaluation. During OGTT in normal C57BL/6J mice, compound 15q reduced blood glucose excursion in a dose-dependent manner. Chronic treatment for 28days with compound 15q improved the serum glucose levels in type 2 diabetic Sprague Dawley rats wherein diabetes was induced by high fat diet and low dose streptozotocin. This suggested that compound 15q is a moderately potent and selective hit molecule which can be further optimized structurally to increase the efficacy and overall pharmacological profile as DPP-4 inhibitor.

Design, synthesis and anti-HIV activity of novel quinoxaline derivatives.

In order to design novel anti-HIV agents, pharmacophore modelling, virtual screening, 3D-QSAR and molecular docking studies were performed. Pharmacophore model was generated using 17 structurally diverse molecules using DISCOtech followed by refinement with GASP module of Sybyl X. The best model containing four features; two donor sites, one acceptor atom and one hydrophobic region; was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥98 were retrieved. The quinoxaline ring which is the bio-isostere of pteridine ring, retrieved as a hit in virtual screening, was selected as a core moiety. 3D-QSAR was carried on thirty five 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested incorporation of hydrophobic, bulky and electronegative groups to increase potency of the designed compounds. 50 quinoxaline derivatives with different substitutions were designed on basis of both ligand based drug design approaches and were mapped on the best pharmacophore model. From this, best 32 quinoxaline derivatives were docked onto the active site of integrase enzyme and in-silico ADMET properties were also predicted. From this data, synthesis of top 7 quinoxaline derivatives was carried out and were characterized using Mass, (1)H-NMR and (13)C-NMR spectroscopy. Purity of compounds were checked using HPLC. These derivatives were evaluated for anti-HIV activity on III-B strain of HIV-1 and cytotoxicity studies were performed on VERO cell line. Two quinoxaline derivatives (7d and 7e) showed good results, which can be further explored to develop novel anti-HIV agents.

Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors.

Dipeptidyl peptidase-4 (DPP-4) is one of the widely explored novel targets for Type 2 diabetes mellitus (T2DM) currently. Research has been focused on the strategy to preserve the endogenous glucagon like peptide (GLP)-1 activity by inhibiting the DPP-4 action. The DPP-4 inhibitors are weight neutral, well tolerated and give better glycaemic control over a longer duration of time compared to existing conventional therapies. The journey of DPP-4 inhibitors in the market started from the launch of sitagliptin in 2006 to latest drug teneligliptin in 2012. This review is mainly focusing on the recent medicinal aspects and advancements in the designing of DPP-4 inhibitors with the therapeutic potential of DPP-4 as a target to convey more clarity in the diffused data.