Computer-aided design of selective COX2 inhibitors: molecular docking of structurally diverse cyclooxygenase-2 inhibitors using FlexX

Motivation: Three-dimensional structures of pharmacologically important macromolecules offer a route to the discovery of new drugs. Understanding the macromolecule-ligand interactions and validation of method used for docking and virtual screening of chemical databases is crucial step in structure-based design. We therefore carried out molecular docking for a set of eighty two structurally diverse COX-1/COX-2 inhibitors including traditional NSAIDs and the recent developed coxibs using FlexX method to find out how good this method differentiate between the active and inactive compounds. Method: FlexX is one of the fast flexible docking method that uses an incremental construction algorithm to place ligands into an active site. The scoring function (empirical binding free energy) of the flexX used to estimate the free binding energy of the protein-ligand complex is called F_score. Results: Reproducibility of the experimental conformations of the bound ligands such as SC-558, indomethacin, flurbiprofen indicates the better performance of FlexX method. Good correlation between the standard FlexX score (F_score) and the COX-2 inhibitory activity (pIC50) was observed. Simple linear regression analysis provided the correlation coefficient values of 0.731 and 0.670 for two classes of COX-2 inhibitors. Conclusions: Flexible docking of eighty two structurally diverse COX-2 inhibitors have been successfully carried out. Some false positives and false negatives were observed but considering the limitations of the available docking programs, the results are encouraging. The detailed analysis of the resulted COX-2-ligand complexes may improve our knowledge in understanding the binding interactions in detail. Thus, this study will be useful for the design of novel COX-2 inhibitors based on docking and the resulted bioactive conformations of the ligands will be useful in building structure-based 3-D QSAR model

Sperm DNA fragmentation: A new guideline for clinicians

Sperm DNA integrity is crucial for fertilization and development of healthy offspring. The spermatozoon undergoes extensive molecular remodeling of its nucleus during later phases of spermatogenesis, which imparts compaction and protects the genetic content. Testicular (defective maturation and abortive apoptosis) and post-testicular (oxidative stress) mechanisms are implicated in the etiology of sperm DNA fragmentation (SDF), which affects both natural and assisted reproduction. Several clinical and environmental factors are known to negatively impact sperm DNA integrity. An increasing number of reports emphasizes the direct relationship between sperm DNA damage and male infertility. Currently, several assays are available to assess sperm DNA damage, however, routine assessment of SDF in clinical practice is not recommended by professional organizations

Copper(II) tetrafluoroborate-catalyzed formation of aldehyde-1,1-di­acetates

Aldehyde 1,1-diacetates are efficiently formed in excellent yields from aldehydes and acetic anhydride under solvent-free conditions at room temperature in the presence of a catalytic amount of copper(II) tetrafluoroborate hydrate

Targeting severe acute respiratory syndrome-coronavirus (SARS-CoV-1) with structurally diverse inhibitors: A comprehensive review

Coronaviruses, which were discovered in 1968, can lead to some human viral disorders, like severe acute respiratory syndrome (SARS), Middle East respiratory syndrome-related (MERS), and, recently, coronavirus disease 2019 (COVID-19). The coronavirus that leads to COVID-19 is rapidly spreading all over the world and is the reason for the deaths of thousands of people. Recent research has revealed that there is about 80% sequence homology between the coronaviruses that cause SARS and COVID-19. Considering this fact, we decided to collect the maximum available information on targets, structures, and inhibitors reported so far for SARS-CoV-1 that could be useful for researchers who work on closely related COVID-19. There are vital proteases, like papain-like protease 2 (PL2pro) and 3C-like protease (3CLpro), or main protease (Mpro), that are involved in and are essential for the replication of SARS coronavirus and so are valuable targets for the treatment of patients affected by this type of virus. SARS-CoV-1 NTPase/helicase plays an important role in the release of several non-structural proteins (nsps), so it is another essential target relating to the viral life cycle. In this paper, we provide extensive information about diverse molecules with anti-SARS activity. In addition to traditional medicinal chemistry outcomes, HTS, virtual screening efforts, and structural insights for better understanding inhibitors and SARS-CoV-1 target complexes are also discussed. This study covers a wide range of anti-SARS agents, particularly SARS-CoV-1 inhibitors, and provides new insights into drug design for the deadly SARS-CoV-2 virus

Therapeutic potential of chemically modified siRNA: Recent trends

Small interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug-like molecules due to poor bioavailability and immunogenic and off-target effects. To overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy

Molecular mechanisms of curcumin and its semisynthetic analogues in prostate cancer prevention and treatment

Primary prostate cancer, also known as prostate adenocarcinoma (PCa), is a devastating cancer in men worldwide. Europe and developing countries of Asia have fewer reported cases of prostate cancer compared to increasing cases in the United States with higher incidence in Black men. Risk factors associated with prostate cancer are aging, genetics, lifestyle, high body mass index as well as carcinogenic exposure to carbon-containing fuels, tobacco, and charbroiled meats. Hormone therapy and radical prostatectomy are commonly implemented treatments. The \u3e 20.000 prostate cancer deaths of 2013 suggest that there exists a need for enhanced chemopreventive and therapeutic agents for prostate cancer treatment. Fruits, vegetables, and red wines contain high levels of polyphenolic levels. Consumption of these products may provide chemoprevetion of PCa. Curcumin, the major compound from the turmeric rhizome Curcuma longa has long been used for medicinal purposes as an antiseptic and wound healing. This review focuses on curcumin\u27s therapeutic effectiveness in vitro and in vivo in prostate cancer models. The review will highlight the mechanisms of actions of curcumin in the signaling pathways of prostate cancer

Zinc(II) perchlorate as a new and highly efficient catalyst for formation of aldehyde 1,1-diacetate at room temperature and under solvent-free conditions

Zinc(II) perchlorate efficiently catalysed the conversion of aromatic, heteroaromatic, and aliphatic aldehydes to 1,1-diacetates under solvent-free conditions at room temperature. It was compatible with other functional groups (e.g., ether, ester, nitro, and cyano) likely to interfere by complex formation with the catalyst. Other anhydrides such as isobutyric, pivalic, and benzoic anhydrides afforded the corresponding 1,1-dicarboxylates and established the generality. The reaction rate was influenced by the steric and electronic nature of the anhydride. The rate of 1,1-dicarboxylate formation was found to follow the order Ac2O > (i-PrCO)2O > (t-BuCO)2O > (PhCO)2O and no 1,1-dicarboxylate formation took place with (ClCH2CO)2O, and (F3CO)2O. During inter- and intra-molecular competition between a ketone and an aldehyde group with Ac2O, 1,1-diacetate formation took place exclusively with the aldehyde group. An 88:12 selectivity was observed for 1,1-diacetate formation in favour of 1-naphthaldehyde during competition with 2-methoxy-1-naphthaldehyde

6-(N-benzoylamino)purine as a novel and potent inhibitor of xanthine oxidase: inhibition mechanism and molecular modeling studies

The inhibition of xanthine oxidase (XO) activity by the purine analogue 6-(N-benzoylamino)purine was evaluated and compared with the standard inhibitor, allopurinol and the parent compound adenine. 6-(N-benzoylamino)purine is a highly potent inhibitor of XO (IC50 = 0.45 μM) and comparable to allopurinol (IC50 = 0.80 μM). Furthermore, 6-(N-benzoylamino)purine neither produced any enzymatic superoxide nor reduced XO by an electron transfer reaction unlike allopurinol. 6-(N-benzoylamino)purine (Ki = 0.0475 μM) is about 10000-fold more potent as a XO inhibitor compared to the only known purine analogue 8-bromoxanthine (Ki = 400 μM). 6-(N-Benzoylamino)purine is a competitive inhibitor of XO and the inhibition was not completely reversed even at 100 μM xanthine concentration. The calculated interaction energy [Ecomplex- (Eligand + Eprotein)] of -30.5, -22.6, and -17.2 kcal/mol, respectively, of 6-(N-benzoylamino)purine, 8-bromoxanthine and the parent compound adenine provided the rationale for the better enzyme inhibitory activity of 6-(N-benzoylamino)purine. To understand the role of the benzamido group in the inhibition process, molecular docking studies were carried out and it was revealed that the hydrogen bonding interactions involving N-7 of the purine ring and the N−H of Arg880, N−H of the purine ring and OH of Thr1010, as well as non-bonded interactions of the benzamido group of 6-(N-benzoylamino)purine with amino acid residues Gly799, Glu802, Phe914, Ala1078, Ala1079 and Glu1261 in the active site of XO play an important role in the stabilization of the E-I complex