Letters in Drug Design & Discovery - Volume 19, Issue 11, 2022

Drug design and discovery is a process that requires high financial costs and is timeconsuming. For many years, this process focused on empirical pharmacology. However, over the years, the target-based approach allowed a significant discovery in this field, initiating the rational design era. In view, to decrease the time and financial cost, rational drug design is benefited by increasing computer engineering and software development, and computer-aided drug design (CADD) emerges as a promising alternative. Since the 1970s, this approach has been able to identify many important and revolutionary compounds, like protease inhibitors, antibiotics, and others. Many anticancer compounds identified through this approach have shown their importance, being CADD essential in any drug discovery campaign. Thus, this perspective will present the prominent successful cases utilizing this approach and entering into the next stage of drug design. We believe that drug discovery will follow the progress in bioinformatics, using high-performance computing with molecular dynamics protocols faster and more effectively. In addition, artificial intelligence and machine learning will be the next process in the rational design of new drugs. Here, we hope that this paper generates new ideas and instigates research groups worldwide to use these methods and stimulate progress in drug design.

Background: Obesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity. Methods: In this present work, a new series of echitamine-inspired indole-based thiazolidinedione hybrid analogues were designed, synthesized, and evaluated for their in vitro PL inhibitory potential. The nature of inhibition has been identified by enzyme kinetic analysis, whereas in silico molecular modelling tools (molecular docking and dynamic studies) were used for the identification of the mode of action at the catalytic site of PL (PDB ID: 1LPB). Fluorescence quenching was used for the identification of the interaction between the potent analogues with PL. Results: The condensation reaction of substituted indole derivatives with TZD in the presence of aqueous KOH resulted in the formation of the titled analogues. Analogues 7k and 7p displayed a potential PL inhibitory activity (IC50 = 11.36 and 11.87 μM, respectively). A competitive mode of PL inhibition was revealed in the enzyme kinetic analysis. A static quenching mechanism was exhibited by the screened agents on PL. The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson’s r - 0.7575, p < 0.05). Moreover, the PL-ligand complexes were stable in the dynamic conditions. Conclusion: Analogue 7k exerted the potential activity, and further studies might result in novel lead molecules.

Background: P7 viroporin in HCV is a cation-selective ion channel-forming protein, functional in the oligomeric form. It is considered to be a potential target for anti-HCV compounds due to its crucial role in viral entry, assembly, and release. Methods: Conserved crucial residues present in HCV p7 protein were delineated from the available literature with a specific focus on the genotypes 3a and 1b prevalent in India. Using the Flex-X docking tool, a library of FDA-approved drugs was docked on the receptor sites prepared around crucial residues. In the present study, we proposed drug repurposing to target viroporin p7, which may help in the rapid development of effective anti-HCV therapies. Results: With our approach of poly-pharmacology, a variety of drugs currently identified as antibiotics, antiparasitic, antiemetic, anti-retroviral, and anti-neoplastic were found to dock successfully on the p7 viroporin. Noteworthy among these are general-purpose cephalosporin antibiotics, leucal, phthalylsulfathiazole, and granisetron, which may be useful in acute HCV infection, and anti-neoplastic sorafenib and nilotinib, which may be valuable in advanced HCV-HCC cases. Conclusion: This study could pave the way for quick repurposing of these compounds as anti-HCV therapeutics.

Background: Tat protein is considered essential for substantial HIV-1 replication, and is also required to break HIV-1 latency, resulting in productive HIV replication. The multifaceted regulatory role of HIV Tat and the fact that it is expressed in the early stages of HIV infection justify its potential as an anti-HIV drug target. Objective: The present study was undertaken with the aim to target HIV-1 Tat protein with natural compounds which could help in identifying potential inhibitors against HIV-1 Tat. Methods: In this study, we compared the binding of Tat protein and Human P-TEFb Tat protein complex (TPC) with phyto-steroids and terpenes to evaluate their potential for HIV-1 treatment. The docking ability of plant products with HIV-1 Tat and TPC was studied with respect to dissociation constant, geometric shape complementary score, approximate interface area, and binding energy using Patch dock and YASARA. Molecular dynamics simulation was set up to investigate the interactions of the natural compounds with Tat protein and human tat protein complex (TPC). Results: The binding energy and dissociation constant of Diosgenin, Catharanthine and Ginkgolide A with Tat and TPC were comparable to antiretroviral drugs, Maraviroc and Emtricitabine. The natural products, Diosgenin, Ginkgolide A and Catharanthine, showed the highest binding energy and were stable with Tat protein and TPC in the entire MD simulation run. Conclusion: The natural products, Diosgenin, Ginkgolide A and Catharanthine, showed highest binding energy and were stable with Tat protein and TPC in the entire MD simulation run. The binding energy and dissociation constant of Diosgenin, Catharanthine and Ginkgolide A with Tat and TPC were comparable to antiretroviral drugs, Maraviroc and Emtricitabine.

Background: The 2019 novel coronavirus disease (COVID-19) has caused a global health catastrophe by affecting the human population around the globe. Unfortunately, there is no specific medication or treatment currently available for COVID-19. Objective: It is extremely important to find effective drug treatment in order to put an end to this pandemic period and return to normal daily life. In this context and considering the urgency, rather than focusing on the discovery of novel compounds, it is critical to explore the effects of existing herbal agents with proven antiviral properties on the virus. Methods: Molecular docking studies were carried out employing three different methods, Glide extra precision (XP) docking, induced fit docking (IFD), and molecular mechanics/generalized born surface area (MM/GBSA), to determine the potential antiviral and antibacterial effects of 58 phytochemicals present in Rosmarinus officinalis, Thymbra spicata, Satureja thymbra, and Stachys lavandulifolia plants against the main protease (M^pro) and angiotensin-converting enzyme 2 (ACE2) enzymes. Results: 7 compounds stood out among all the molecules, showing very high binding affinities. According to our findings, the substances chlorogenic acid, rosmarinic acid, and rosmanol exhibited extremely significant binding affinities for both M^pro and ACE2 enzymes. Furthermore, carnosic acid and alphacadinol showed potent anti-M^pro activity, whereas caffeic acid and carvacrol exhibited promising anti- ACE2 activity. Conclusion: Chlorogenic acid, rosmarinic acid, rosmanol, carnosic acid, alpha-cadinol, caffeic acid, and carvacrol compounds have been shown to be powerful anti-SARS-CoV-2 agents in docking simulations against M^pro and ACE2 enzymes, as well as ADME investigations.

A new series of bis-chalcones 5-10 has been prepared by the condensation reaction of one equivalent of bis(acetophenones) 3a-f with two equivalents of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 4. The newly prepared compounds 5-10 have been fully characterized and evaluated as in vitro anticancer agents against a panel of human cancer cell lines A431, A549, PC3, and a normal human skin fibroblast BJ1. Aims: The current work is designed to explore the anti-cancer activity of novel bis-chalcones incorporating a 1,3-diphenyl-1H-pyrazole moiety. Background: Chalcones represent one of the most important organic compounds that have been attracting the interest of many researchers in drug discovery. Objective: The present study was carried out to explore anti-cancer activity of novel bis-chalcones incorporating a 1,3-diphenyl-1H-pyrazole moiety as in vitro and in silico studies. Materials and Methods: We used the condensation reaction to prepare bis-chalcones incorporating 1,3- diphenyl-1H-pyrazole moiety. The MTT Assay, Anti-cancer activity, Gene expression, DNA Fragmentation, DNA Damage, and Molecular docking were investigated. Results: Compounds 5 and 9 were found to be the most promising compounds in the prepared series with IC50 (50.3 and 50.1 μg/ml, respectively) against epidermoid cancer cell line A431 compared to doxorubicin as a reference drug. Conclusion: All of these results showed that chalcones 5 and 9 have promising anti-cancer properties without cytotoxic effect, which could make them a promising active component for further studies.

Background: The emergence of COVID-19 as a fatal viral disease encourages researchers to develop effective and efficient therapeutic agents. The intervention of in silico studies has led to revolutionary changes in the conventional method of testing the bioactivity of plant constituents. Objective: The current study deals with the investigation of some traditional immunomodulators of plant origin to combat this ailment. Materials and Methods: A total of 151 phytomolecules of 12 immunomodulatory plants were evaluated for their inhibitory action against the main protease (PDB ID: 7D1M) and NSP15 endoribonuclease (PDB ID: 6WLC) by structure-based virtual screening. In addition, the promising molecules with ligand efficiency of more than -0.3(kcal/mol)/heavy atoms were further predicted for pharmacokinetic properties and druggability using the SwissADME web server, and their toxicity was also evaluated using Protox-II. Results: Myricetin-3-O-arabinofuranoside of cranberry plant was found to be the most potential candidate against both enzymes: main protease (–14.2 kcal/mol) and NSP15 endoribonuclease (–12.2 kcal/mol). Conclusion: The promising outcomes of the current study may be implemented in future drug development against coronavirus. The findings also help in the development of lead candidates of plant origin with a better ADMET profile in the future.

Background: Hypothyroidism is a common disorder due to inadequate thyroid hormone secretion. In patients with hypothyroidism, levothyroxine (LT4) is the treatment of choice, and tablets are the most common dosage form. However, the main limitation of tablet LT4 is malabsorption. Objective: This study intends to develop a new dosage form of percutaneous drug delivery for levothyroxine. Absorption of levothyroxine sodium through the application of gel formulation was studied using a hypothyroidism rat model. Methods: A formulation of levothyroxine sodium gel was developed and selected. In vitro transdermal experiments were performed using the vertical Franz diffusion pool method, and gel formulation was used for animal research (hypothyroidism rats model). Total 30 rats were randomly divided into 6 groups, and one was the normal control group. The other 5 groups were prepared as hypothyroidism models. After applying different doses of gel preparation to the rat model, we measured serum total thyroxine (TT4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) using fluorescence determination of luminescence immunoassay. Results: The optimum formulation of levothyroxine gels comprised 20% polyvinyl alcohol (PVA), 5% glycerol, 2% azone, and 6% oleic acid. The application of levothyroxine sodium gel resulted in quick and smooth action so that the predicted level of the normal control group could be reached within 2 weeks, and it lasted steadily for 8 weeks. Conclusion: This research study successfully developed and tested an optimal formulation of levothyroxine gel with therapeutic benefit on hypothyroidism in rats.