Computer Assisted Models for Blood Brain Barrier Permeation of 1, 5-Benzodiazepines.

AIM: To generate and validate predictive models for blood-brain permeation (BBB) of CNS molecules using the QSPR approach. BACKGROUND: Prediction of molecules crossing BBB remains a challenge in drug delivery. Predictive models are designed for the evaluation of a set of preclinical drugs which may serve as alternatives for determining BBB permeation by experimentation. OBJECTIVE: The objective of the present study was to generate QSPR models for the permeation of CNS molecules across BBB and its validation using existing in-house leads. METHODS: The present study envisaged the determination of the set of molecular descriptors which are considered significant correlative factors for BBB permeation property. Quantitative Structure- Property Relationship (QSPR) approach was followed to describe the correlation between identified descriptors for 45 molecules and highest, moderate and least BBB permeation data. The molecular descriptors were selected based on drug-likeness, hydrophilicity, hydrophobicity, polar surface area, etc. of molecules that served the highest correlation with BBB permeation. The experimental data in terms of log BB were collected from available literature, subjected to 2D-QSPR model generation using a regression analysis method like Multiple Linear Regression (MLR). RESULTS: The best QSPR model was Model 3, which exhibited regression coefficient as R2= 0.89, F = 36; Q2= 0.7805 and properties such as polar surface area, hydrophobic hydrophilic distance, electronegativity, etc., which were considered key parameters in the determination of the BBB permeability. The developed QSPR models were validated with in-house 1,5-benzodiazepines molecules and correlation studies were conducted between experimental and predicted BBB permeability. CONCLUSION: The QSPR model 3 showed predictive results that were in good agreements with experimental results for blood-brain permeation. Thus, this model was found to be satisfactory in achieving a good correlation between selected descriptors and BBB permeation for benzodiazepines and tricyclic compounds.

Development of lipoprotein-drug conjugates for targeted drug delivery.

Tumour targeting approaches used in cancer chemotherapy offers prolonged, localized, and protected drug interaction with the diseased tissue with minimal side effects and systemic toxicity, which are accountable for the failure of chemotherapy using conventional delivery systems. The purpose of the present study is to develop an anticancer targeted drug delivery system using synthesized lipoproteins with the integration of quality by design approach. Lipoprotein structures were designed, and quality by design approach was implemented to select variables for optimization. Further, the lipoproteins were synthesized and characterized by physicochemical properties. Physical composites of synthesized lipoproteins with the drug (tablets) were prepared and evaluated for post-compression parameters. Moreover, drug-lipoprotein chemical conjugates were synthesized and characterized for physicochemical properties, including cellular drug uptake and cytotoxicity study on HaCaT cancer cells. Synthesized lipoproteins showed good swelling capacity but poor flowability. Nuclear magnetic resonance and infrared spectroscopy of conjugates showed characteristic peaks. Tablets from all batches extended the drug release up to 12 h. All synthesized conjugates showed improved cellular drug uptake (up to 86.1%) and inhibition (87.39%) of HaCat cancer cells. These findings explored the possible use of synthesized lipoproteins in the development of anti-cancer drug formulation against HaCat cancer cells.Communicated by Ramaswamy H. Sarma.

Identification and Investigation of Chalcone Derivatives as Calcium Channel Blockers: Pharmacophore Modeling, Docking Studies, In vitro Screening, and 3D-QSAR Analysis.

BACKGROUND: The chalcones were reported to have many biological activities by showing affinity towards many enzymatic targets. The effect of nitric oxide (NO) on calcium channel was extensively studied in different animals; the study was also carried out for NO donor drug and its effect on calcium channel. Till date, the inhibition of calcium channel is of prime importance in the medicinal chemistry to discover newer vascular smooth muscle relaxant drugs. OBJECTIVE: The main objective of this work is to carry out in silico and in vitro evaluation of NO donor chalcones for calcium channel blocking potency. METHODS: The present work includes in silico evaluation of chalcone derivatives for calcium channel blocking potency. The promising scaffolds were identified after pharmacophore modeling and docking study. The in vitro screening of 21 lead molecules for calcium channel blocking potency was carried out on pulmonary veins of adult goat, IC50 values were determined and 3D QSAR was performed. RESULTS: The pharmacophore modeling revealed that hydrogen bond donor, hydrogen bond acceptor, and hydrophobic groups are important features for calcium channel blocking activity. The docking study revealed the existence of hydrophobic, hydrogen bond and Vander wall's interactions between amino acid residues and ligands. The in vitro screening showed that the compounds AI6, Ca2, and D8 were potent, produced 4.756, 3.608 and 5.211 µM of IC50 respectively, whereas the standard Nifedipine showed the potency of 1.304 µM of IC50. The 3D QSAR study explained the importance of different steric and electrostatic parameters and their correlation for L type calcium channel blocking activity. CONCLUSION: This study showed that the chalcone scaffold with NO donor capacity is promising for designing novel calcium channel blockers to treat vascular disorders.

Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials.

BACKGROUND: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance. OBJECTIVES: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design. METHODS: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures. RESULTS: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity. CONCLUSION: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Development of 'S', 'N' Heterocycles as Antimycobacterials Targeting Fatty Acid Biosynthesis.

BACKGROUND: Mycobacterium tuberculosis is a causative organism of tuberculosis, which is the most deadly disease after cancer in the current decade. The development of multidrug and broadly drug- resistant strains makes the tuberculosis problem more and more critical. In the last 40 years, only one molecule is added to the treatment regimen. Generally, drug design and development programs are targeted proteins whose function is known to be essential to the bacterial cell. OBJECTIVES: Here are the development of 'S', 'N' heterocycles as antimycobacterials targeting fatty acid biosynthesis are reported. MATERIALS AND METHODS: In the present communication, rational development of anti-mycobacterial agent's targeting fatty acid biosynthesis has been done by integrating the pocket modeling and virtual analysis. RESULTS: The identified potential 33 lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like IR, NMR spectroscopy and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds have shown profound antimycobacterial activity. CONCLUSION: In this present communication, we found that 3c, 3f, 3l and 4k molecules had expressive desirable biological activity and specific interactions with fatty acids. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates having fewer side effects.

Optimization of Thiazolidone Scaffolds Using Pocket Modeling for Development of Potential Secretory System Inhibitors of Mycobacterium tuberculosis.

OBJECTIVES: Mycobacterium tuberculosis is the causative organism of tuberculosis, which is the most lethal disease after cancer in the current decade. The development of multidrug and broadly drug-resistant strains is making the problem of tuberculosis more and more critical. In the last 40 years, only one molecule has been added to the treatment regimen. Generally, drug design and development programs target proteins whose function is known to be essential to the bacterial cell. M. tuberculosis possesses specialized protein export systems like the SecA2 export pathway and ESX pathways. MATERIALS AND METHODS: In the present communication, rational development of an antimycobacterial agent's targeting protein export system was carried out by integrating pocket modeling and virtual analysis. RESULTS: The 23 identified potential lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like infrared and nuclear magnetic resonance spectroscopy, and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds showed profound antimycobacterial activity. CONCLUSION: We found that Q30, M9, M26, U8, and R26 molecules had significant desirable biological activity and specific interactions with Sec of mycobacteria. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates with fewer side effects.