Letters in Drug Design & Discovery - Volume 13, Issue 10, 2016

Recently biopharmaceuticals have been showing a great number of investments. β- Galactosidase is an example of this increasing market, since this is an enzyme that can be used for those who are intolerant to lactose and are not able to eat or drink milk and dairy products. The main difficulty of working with enzymes is that it can lost its activity very easily, so pre-formulation tests have to be ran in order to define the suitable excipients for a formulation that will not degrade the Active Principal Ingredient (API). Computational methods such as molecular docking have been used to conduct these pre-formulation tests and then pedict the energy of interactions between protein and excipient, which are the best substances to be used on a pharmaceutical formulation. Seven excipients were divided into groups and tested using protocols of simulation that could predict the final energy found after all the interactions present in the excipients-enzyme binding, what represents a faster and easier approach for the development of a pharmaceutical since a range of excipients are pre-selected while others are excluded with only a single set.

Lipinski`s Rule for central nervous system drugs (RoCNS), reported in 1999, predicts that poor absorption or permeation is more likely when there are more than three hydrogen bond donors (HBD), seven hydrogen bond acceptors (HBA), molecular weight (MW) is greater than 400 Da and CLog P is greater than five. The objective of this work was to evaluate the applicability of RoCNS for drugs approved from 1985 to 2014. Calculated physicochemical properties of central nervous system (CNS) drugs were compared to parameters established by the rule. From 1985 to 1999, 48 drugs were introduced for clinical therapy and 31% unsuited the RoCNS (among which six drugs did not fit within the determined CLog P, four the MW, four the HDA and two the HBD). From 2000 to 2014, 38 drugs were introduced and 32% violated RoCNS parameters (among which eight drugs did not fit within the determined MW, four the HBD, two the HBA and one the CLog P). These findings suggest that even though drugs introduced to the market after RoCNS publication showed a tendency to apply the rule, the application of the rule is similar for both periods. Examining the applicability of the RoCNS, it may serve as a guide for medicinal chemists designing future CNS-active small molecules.

Several classes of anti-neoplastic drugs, in particular, those targeting protein kinase mTOR, topoisomerases and histone deacetylases, along with yet unknown pathways which inhibition is beneficial in cancer treatment, can augment expression of encoded by recombinant adenoviruses transgenes. We used enhancement of transgene expression encoded by recombinant adenovirus as a sensor enabling simultaneous identification of compounds with the above-mentioned diverse activities, and developed principles of screening assay for primary identification of candidate compounds with anti-neoplastic properties. The assay is suited for high-throughput application, with homogeneous format and green/blue fluorescence readout.

In search of new inhibitors of the Ser/Thr protein kinase PknB from Mycobacterium tuberculosis we carried out a structure-based virtual screening study to identify ATP-competitive inhibitors of this enzyme. These studies point out that N-phenylmethylindole-2-carboxamide is a promising scaffold for the development of new PknB inhibitors. We synthesized a small set of analogue compounds to assess the pharmacophore structural requirements and to optimize the inhibitory activity against PknB. This strategy led to the identification of compound 3, endowed with an IC50 of 20 μM, which provides a novel scaffold for further improvement of PknB inhibitors.

A series of nineteen 2-aryl-4H-chromen-4-one derivatives 2a-2s were synthesized and evaluated for their antiviral activity against Chikungunya virus (LR2006_OPY1) in Vero cell culture by CPE reduction assay. Three compounds 2a, 2b and 2g, were found to be active at concentration of (IC50) 0.44 μM, 0.45 μM and 2.02 μM, respectively. Compounds having heterocyclic ring 2a and 2b at the 2nd position of the chromenone were found to be potent inhibitor of ChikV. Cytotoxicity studies were performed using Vero cell culture, compounds 2a and 2b exhibited SI of >100. Molecular docking simulation has been carried out to understand the possible mechanism of action.

Atherosclerosis is a fatal disease for decades, which was thought to be the basis onset of many other cardiovascular diseases. Its pathogenesis is complex, mainly for the chronic vascular inflammation symptoms caused by abnormal lipid metabolism. Inflammation has been recognized as the pivotal role during every step of atherosclerosis. In view of the complication of its pathogenic process, the multi-target medication sometimes is more effective, less side effect and could reduce tolerance which should be another reasonable strategy for anti-atherosclerosis. Sphingomyelin synthase (SMS) is a potential therapeutic target for atherosclerosis treatment, while secretory phospholipase A2 (sPLA2) have been studied as a target of atherosclerosis treatment which plays an important role in the genesis and development of its progress of atherosclerosis. Based on the complex pathogenesis of atherosclerosis, we focused on two key enzymes in this process—SMS and sPLA2. We combined with the existing QSAR of the inhibitors of SMS and sPLA2 and rational multi-target drug design ideas, three series of dual inhibitors of sPLA2 and SMS were designed by linking or fusing SMS inhibitor fragment Ly18 (N-pyridine-3-amide moiety) with sPLA2 inhibitor fragment (indole- 3-acetamide structure) by 3-6 carbon chain as novel dual-functional inhibitors series 1-3. Series 2 and 3 reserved benzyl in sPLA2 or SMS pharmacophore respectively, while series 1 was de-benzyl in order to decrease the molecular weight. Eleven target molecules were synthesized and bio-assayed in vitro. The results showed compounds 3a-3d provided inhibitory activities against SMS2 and 2a-2d exhibited the sPLA2 inhibition activities. The compound 3c showed equivalent activities of both SMS and sPLA2 which would be a potential leading compound of dual inhibitor against atherosclerosis.

Frequent emergence of influenza virus strains resistant to current neuraminidase inhibitors is a global threat and demands for the discovery of new potent inhibitors. Virtual screening techniques have proved to be an effective approach in drug discovery. In this study, we present an approach to further enhance the potency of the typical pharmacophore-based virtual screening method by incorporating a MM/GBSA per-residue energy contribution footprint from molecular dynamics simulation, as opposed to the typical use of docking scores as a frontline screening strategy. The MM/GBSA per-residue energy footprint with highest contribution to the binding free energy was mapped on the reference drug and used to screen for compounds sharing structural similarity with the reference drug. The proposed approach was generated and used to screen the ZINC database for potent inhibitors against influenza neuraminidase. Seven of the novel compounds identified by the proposed approach, with ZINC18142090 being the top-ranked compound, showed higher binding affinities compared to that of known neuraminidase inhibitors zanamivir, oseltamivir and laninamivir. These novel compounds also formed interactions with the conserved active site residues Arg152, Arg292, Asn294, Arg371, Ile222, Arg224, Glu227, Glu276 and Glu277, thus implying a conserved selectivity and binding mode adopted by the obtained compounds. A strategic computational approach presented in this study could serve as a beneficial tool to enhance native virtual screening as well as novel drug discovery.

Yellow fever is a major problem associated with the health particularly in the Africa and South America region. In last few years scientist focus on in silico approach before synthesizing a compound to accelerate the drug discovery process. In the present study a series of 20 compounds of imidazole-4, 5- and pyrazine-2,3- dicarboxamides derivatives having anti yellow fever activity were subjected QSAR analysis using 2D PaDEL descriptors available online. Three different splitting techniques namely activity sorting, distance based and Kennard stone based splitting were used to divide the whole data set and GFA was used a statistical method to develop a model to investigate the physicochemical and structural requirement of potential yellow fever virus inhibitor. All the models are statistically robust both internally and externally (Q2Loo:0.605-0.739, R_((pred))^2: 0.711-0.934) with low RMSEP (0.106-0.250) values. Additionally the full model shows statistically significant Q2Lmo value of 0.684. The activity mostly affected by polarizabilities, electro negativities as well as charges in the compounds indicates the importance of heterocyclic ring system attached. Finally the randomization results indicate the models are not by chance.

P. carinii dihydrofolate reductase (PcDHFR) inhibitors are used for the treatment of P. carinii pneumonia (PCP) in humans with acquired immunodeficiency syndrome (AIDS). Translocation comparative molecular field vector analysis (Topomer CoMFA) 3D-QSAR and molecular docking were applied for a series of pyrimidine derivatives. 64 Pyrimidine derivatives were analyzed and the relationship between the structures and bioactivities was explored. Topomer CoMFA was used to build 3D-QSAR model, the results show that cross-validation q2 = 0.721, SDCV = 0.52, the non-crossvalidated r2 = 0.922, SD = 0.28, and the correlation coefficient of external validation Q2 ext = 0.934, this indicated that model generated form Topomer CoMFA was reasonable, and had good prediction ability. The mechanism of action of drug was studied by molecular docking. It showed that the pyrimidine compounds and GLU32, ILE123, LYS37 sites of PcDHFR have interactions. These results have provided an insight for the design of new potent inhibitors of PcDHFR.

A series of aminoguanidine derivatives bearing a 1,3,4-oxadiazole or piperazine moiety has been synthesized and fully characterized together with a series of 3-amino-1,2,4-triazole derivatives, and the resulting compounds were evaluated for their anti-bacterial activity. Most of these compounds showed broad-spectrum antibacterial activities against both Gram-positive and Gram-negative bacteria with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values in the range of 1–64 μg/mL, including multidrug-resistant clinical isolates and a fungus. Notably, compounds 19e and 19f exhibited higher levels of activity than gatifloxacin and moxifloxacin against several methicillin-resistant Staphylococcus aureus (3167 and 3506) and quinolone-resistant S. aureus (3505 and 3519) strains with MIC and MBC values in the range of 1–2 µg/mL. These two compounds also displayed significant antifungal activities with MIC values of 1 μg/mL against Candida albicans 7535, which were equivalent to the MIC value of the standard drug fluconazole. These results therefore indicate that aminoguanidine derivatives that do not contain a piperazine moiety are interesting scaffolds for the development of novel antibacterial agents.

The synthesis of new hybrid compounds containing several heterocyclic groups namely norfloxacine, 1,2,4-triazole, 1,3,4-oxadiazole, piperazine, morpholine, thiomorpholine, 1,3,4- thiadiazole etc. was performed by conventional and successfully optimized microwave assisted techniques. The effect of acid catalyst on one pot tricomponent Mannich reaction was investigated as well. The structures of newly synthesized compounds were eluciated on the basis of spectroscopic techniques. Also, the synthesized compounds were screened for their antimicrobial activities and most of them were found to possess good-moderate antimicrobial activity.

Facile synthesis of natural aurones, rugaurone A (1a), gramflavonoid A (1b) and their novel derivatives (1c-1o) is accomplished in good to high yields with exceptional Z-selectivity (≥ 97%) from the commercially available starting materials. Herein, practically improved method was developed for the synthesis of common key intermediate, 5,6-dimethoxybenzofuran-3(2H)-one (5). Later, their nitric oxide (NO) production inhibition effects were estimated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages as an indicator of anti-inflammatory activity. All compounds exhibited weak to good strength against NO production in a concentration-dependent manner and none of the compound showed significant cytotoxicity against macrophages at the highest (10 μM) concentration. The IC50 values are showed in the range from 3.39 to 19.55 μM. Among the 15 aurones synthesized in this study, 3 compounds that is compound 1g (63.98%) followed by compound 1o (49.07%) and rugaurone A (1a) (41.72%) showed the maximum inhibitory activity with respective IC50 values of 4.50 μM, 4.98 μM and 3.39 μM compared to L-NMMA (IC50 = 5.19 μM), which was used as a standard NO inhibitor. This study suggests that compounds 1g, 1o and 1a may serve as favorable structures for further development of NO production-targeted anti-inflammatory agents.

A kind of novel hybrid particles (ZCa: Zein/CaCO3) for delivering water-soluble drugs have been prepared by solvent-nonsolvent phase separation method. The obtained ZCa hybrid particles were characterized by DLS, FT-IR spectra and SEM. ZCa hybrid particles have favorable dispersibility. The particle size and shape could be controlled by Zein/CaCO3 mass ratio, with the average size of ZCa hybrid particles being close to 200 nm. Using RB as water-soluble model drug, drug loading and release behaviors of ZCa hybrid particles were investigated. Compared with the pure zein particles, the encapsulation efficiency of ZCa was enhanced obviously, which reached 75.7%. The release ratio of RB in RB@ZCa could be controlled by pH value and by the content of CaCO3. ZCa was also applied to carry and release Dox, anticancer drug, and the cumulative release ratio of Dox@ZCa was obviously enhanced. The cumulative release ratio of Dox@ZCa reached 89 %. ZCa hybrid particles are a promising candidate in nutraceuticals and drugs delivery system.