Waseem Ahmad Ansari

In this study, a new series of chalcone derivatives containing an oxindole moiety to evaluate their physico-chemical properties, pharmacokinetic profiles and in silico biological potential. The designed derivatives 3a-d were obtained via a condensation reaction between 5-halo-isatin and substituted acetophenones using sodium ethoxide under moderate reaction conditions. The structures of the synthesized chalcone derivatives were confirmed using 1H NMR, 13C NMR and HRMS. The in silico evaluations were performed using established database platforms, including SwissADME and admetLAB 3.0, to assess their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. All the compounds exhibited favourable drug-likeness, low predicted toxicity and compliance with Lipinski’s rule of five, suggesting their potential as orally active therapeutic agents. Molecular docking studies were also carried out to assess the binding affinities of compounds 3a-d against cancer-related target proteins such as PDGFRα (PDB ID: 9GZH) and VEGFR2 (PDB ID: 4ASD). Compounds 3b and 3d demonstrated the most promising binding energies (–11.973 and –7.726 kcal/mol, respectively), outperforming the reference drug, sunitinib. The docking results revealed key hydrogen bonding and hydrophobic interactions, offering insights into the stability of the compounds within the active sites of the target proteins.

Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.

Visceral leishmaniasis (VL) is caused byLeishmania donovani(Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target againstL. donovaniin the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high‐throughput virtual screening of 8630 ZINC database ligands againstLeishmania donovaniornithine decarboxylase (LdODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, −10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine).In‐silicofindings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.

Due to the lack of approved vaccines against Cutaneous Leishmaniasis (CL), chemotherapy is the only treatment option. Presently, none of the current CL drugs have high levels of efficacy and safety profiles. Thus, the development of new and safer drugs is urgently needed. Drug repurposing can be used for the development of new therapeutic activities. Phosphomannomutase (PMM) has become highlighted as a potential drug target due to its important role in the biosynthesis of glycoconjugates which is essential for parasite virulence. To identify new promising lead molecules, we have performed virtual screening of 8,500 drugs and selected 46 drugs for docking simulation through the Glide module of Schrodinger software. The saquinavir and grazoprevir showed the highest binding affinity (-10.144 and -10.131 kcal/mole). To find the stability of both complexes, molecular dynamics (MD) simulation were performed at 100ns. The grazoprevir-2i54 and saquinavir-2i54 complexes showed good stability in the active site of the receptor. It could be an alternative drug for the treatment of CL.

The present study explores the efficacy of plant-derived natural products (PDNPs) against spike glycoproteins (S-glycoprotein) of SARS-CoV-2 variants using molecular docking, ADMET, molecular dynamics (MD) simulation and density-functional theory (DFT) analysis. In all, 100 PDNPs were screened against spike glycoprotein of SARS-CoV-2 variants, namely alpha (B.1.1.17), beta (B.1.351), delta (B.1.617), gamma (P.1) and omicron (B.1.1.529). Results showed that rutin, EGCG, hesperidin, withanolide G, rosmarinic acid, diosmetin, myricetin, epicatechin and quercetin were the top hit compounds against each of the SARS-CoV-2 variants. The most active compounds, rutin, hesperidin, EGCG and rosmarinic acid gave binding scores of −10.2, −8.1, −8.9, −8.3 and −9.2 kcal/mol, against omicron, delta, alpha, beta and gamma variants, respectively. Further, the stability of docked complexes was confirmed by the analysis of molecular descriptors (RMSD, RMSF, SASA, Rg and H-bonds) in molecular dynamic simulation analysis. Moreover, the physiochemical properties and drug-likeness of the tested compounds showed that they have no toxicity or carcinogenicity and may be used as druggable targets. In addition, the DFT study revealed the higher activity of the tested compounds against the target proteins. This led us to conclude that rutin, hesperidin, EGCG and rosmarinic acid are good candidates to target the S-glycoproteins of SARS-CoV-2 variants. Further, in vivo and clinical studies needed to develop them as drug leads against existing or new SARS-CoV-2 variants are currently underway in our laboratory.

Background: The newly emerged delta and omicron variants of severe acute respiratory syndrome coronavirus (SARS-CoV-2) have affected millions of individuals globally with increased transmissible and infectivity rates. Although, numerous vaccines are available or under clinical trials to combat the SARS-CoV-2 and its variant, still, a therapeutic agent is awaited. Objective: The present work is focused on rigorous screening of chemical constituents of Azadirachta indica (A. indica) against delta and omicron variants of SARS-CoV-2 via inhibition of S-glycoprotein. Methods: Total, 10 compounds of A. indica were subjected to molecular docking and pharmacophore modeling studies against the S-glycoprotein of delta and omicron variants of SARS-CoV-2. Furthermore, homology modeling was performed for omicron S-glycoprotein with the help of SWISS-MODEL and aligned by PyMOL software. Later on, the residues of protein were verified in the allowed region via Ramachandran plot. In addition, our docking results have also been validated by MMGBSA binding free energy calculations. Results: Our computed study demonstrated that nimbolinin B12-methyl ether and nimbidinin showed promising docking scores (> -6.0) as compared to docking scores (< 6.0) of reference drug ‘camostat’ against S-glycoproteins of both delta and omicron variants. Redocking by using MMGBSA calculation also reveals that both these compounds can effectively bind within the pockets of said protein receptors Conclusion: Nimbolinin B12-methyl ether and nimbidinin have potent anti-SARS-CoV activity against delta and omicron variants and thus, A. indica might be a useful source for developing novel anti-SARSCoV- 2 therapeutic agents.

Background: Coronavirus disease-2019 (COVID-19) has recently emerged as a pandemic respiratory disease with mild to severe pneumonia symptoms. No clinical antiviral agent is available so far. However, several repurposing drugs and vaccines are being given to individuals or in clinical trials against SARS-CoV-2 Objective: The aim of this study is to uncover the potential effects of Luteolin (Lut) as an inhibitor of SARS-CoV2 encoded proteins via utilizing computational tools. Method: Molecular modelling to unfold the anti-SARS-CoV2 potential of Lut along with reference drugs namely remdesivir and nafamostat was performed by the use of molecular docking, molecular dynamic (MD) simulation, absorption, distribution, metabolism, excretion, toxicity (ADMET) and density functional theory (DFT) methods against the five different SARS-CoV-2 encoded key proteins and one human receptor protein. The chemical reactivity of Luteolin is done through prediction of HOMO-LUMO gap energy and other chemical descriptors analysis. Results: In the present study, Lut binds effectively in the binding pockets of spike glycoprotein (6VSB), ADP phosphatase of NSP3 (6W02), and RNA dependent RNA polymerase (7AAP) protein receptors with significant values of docking scores -7.00, -7.25, and -6.46 respectively as compared to reference drugs remdesivir and nafamostat. Conclusion:: Thus, Lut can act as a therapeutic agent and is orally safe for human consumption as predicted by molecular modelling against SARS-CoV-2 in the treatment of COVID-19.

Among the JAKs, JAK3 is the most important target for the treatment of inflammatory diseases because its inhibition showed the utmost immunosuppression. Many JAK3 inhibitors are already available but most of them showed acquired drug resistance or objectionable side effects. To prevent inflammatory diseases, novel and superior drugs are needed. The drug repositioning is an alternate process that can be used as a fast-track approach. Drugs already approved by regulatory agencies have well-known pharmacokinetics and safety profile. When a new therapeutic activity has been identified, the entities can be rapidly advanced into clinical trials. To identify new promising lead molecules, we have selected 1150 approved drugs for their potential to be repurposed for inflammatory diseases. The library of approved drugs was obtained from zinc data base and JAK3 (PDB ID: 3LXK) was retrieved from protein data bank and used for molecular docking simulation and protein-ligand interaction analysis. The virtual screening of full library of drugs by AutoDock Vina version PyRx 0.8 and selected 100 drug molecules and further filtered through click-1 docking software. The binding affinity of top 8 drugs ranges between –10.3 to –7.8 kcal/mole. The threshold binding affinity of fluspirilene for JAK3 was –10.3 kcal/mole was repurposed to be promising drug candidate for inflammatory diseases. The results showed that fluspirilene has best docking interaction with JAK3 (PDB ID: 3LXK) and molecular dynamics simulation was also carried out to investigate structural conformations and to explore the key amino acids in the interaction between target and ligands. In conclusion, fluspirilene could be one of the alternative drugs for the treatment of inflammatory diseases.

The recent outbreak “Coronavirus Disease 2019 (COVID-19)” is caused by fast-spreading and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). This virus enters into the human respiratory system by binding of the viral surface spike glycoprotein (S-protein) to an angiotensin-converting enzyme2 (ACE2) receptor that is found in the nasal passage and oral cavity of a human. Both spike protein and the ACE2 receptor have been identified as promising therapeutic targets to develop anti-SARS-CoV2 drugs. No therapeutic drugs have been developed as of today except for some vaccines. Therefore, potent therapeutic agents are urgently needed to combat the COVID-19 infections. This goal would be achieved only by applying drug repurposing and computational approaches. Thus, based on drug repurposing approach, we have investigated 16 bioactive components (1–16) from different nasal spray solutions to check their efficacies against human ACE2 and SARS-CoV2 spike proteins by performing molecular docking and molecular dynamic (MD) simulation studies. In this study, three bioactive components namely ciclesonide (8), levocabastine (13), and triamcinolone acetonide (16) have been found as promising inhibitory agents against SARS-CoV2 spike and human ACE2 receptor proteins with excellent binding affinities, comparing to reference drugs such as nafamostat, arbidol, losartan, and benazepril. Furthermore, MD simulations were performed (triplicate) for 100 ns to confirm the stability of 8, 13, and 16 with said protein targets and to compute MM-PBSA-based binding-free energy calculations. Thus, bioactive components 8, 13, and 16 open the door for researchers and scientist globally to investigate them against SARS-CoV2 through in vitro and in vivo analysis. Graphical abstract

Cutaneous leishmaniasis (CL) is caused by the protozoan parasite L. maxicana is one of the major parasitic diseases throughout the world. Due to the lack of approved vaccines against CL, chemotherapy is the only modern treatment. These treatments have some major consequences including prolonged treatment, parenteral administration, tolerability, teratogenicity, etc. Presently, none of the current CL drugs have high levels of efficacy. Thus, the development of new and safer drugs possessing cost-effective, efficacious, oral and short course drugs is urgently needed. Drug repurposing is another method that can be used for the development of new therapeutic activities.When a new therapeutic activity would have been identified, the entities could be rapidly advanced into clinical trials. Phosphomannomutase (PMM) has become highlighted as potential drug targets due to its important role in the biosynthesis of glycoconjugates.These glycoconjugates are essential for parasite virulence.To identify new promising lead molecules, we have picked 8500 approved drugs for their potential to be repurposed for CL. The library of approved drugs was obtained from Zinc data-base and PMM structure (PDBID: -2i54) was retrieved from protein data bank and used for molecular docking simulation and protein-ligand interaction analysis. The protein structure was validated by the Procheck Ramachandran plot. The virtual screening of the full library of drugs by AutoDock Vina version PyRx 0.8 and selected 46 drug molecules and docking simulations were performed through Glide module of Schrodinger software. Saquinavir and Grazoprevir showed the highest binding affinity -10.144 and -10.131 kcal/mole respectively, was repurposed to be promising drug candidates for CL. To find the stability of complexes (saquinavir-2i54 and grazoprevi-2i54) were performed 100ns molecular dynamics simulation. In the molecular dynamics simulation trajectories of both complexes were analyzed. The results of grazoprevir-2i54 and saquinavir-2i54 complex were showed good stability in the active site of receptor. In conclusion, grazoprevir and saquinavir could be the alternative drugs for the treatment of CL.