Mohammad Haris Siddiqui

Computer Aided Drug Design: Success and Limitations.

Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier

Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included.

Elucidation of Antiangiogenic Potential of Vitexin Obtained from Cucumis sativus Targeting Hsp90 Protein: A Novel Multipathway Targeted Approach to Restrain Angiogenic Phenomena

BACKGROUNDnAngiogenesis involves the process of sprouting of microvessels from preexisting microvasculature and is held responsible for the growth, malignancy and metastasis of cancer. Heat shock protein Hsp90 has been proven responsible for indirectly inducing multiple pathways leading to angiogenesis and metastasis in cancer. Recent researches shift towards proposing novel phytochemicals as possible antiangiogenic agents.nnnOBJECTIVEnThe study aims towards Virtual screening of compounds from Cucurbitaceae family and their Druglikeliness and PreADMET filtering in search of potent lead as Vitexin, targeting Hsp90 and hence restraining angiogenesis.nnnMATERIALS AND METHODSnStructures of phytochemicals from Cucurbitaceae family were retrieved from PubChem database and were converted into suitable 3-D structures. The target protein, Hsp90 was retrieved from RCSB Protein Data Bank. Phytochemicals of Cucurbitaceae family were filtered through enumerated Lipinskis rule of five and ADMET toxicity profiling and the filtered compounds were further taken forward for molecular docking analysis and interaction studies using AutoDock Tools 4.0.nnnRESULTSnThe docking results revealed Vitexin, a prominent glycosylated natural flavonoid, showing promising inhibitory potential against Hsp90 with binding energy of -8.80 kcal/mole and Ki 353.24 nM as compared to its known inhibitor Ganetespib having binding energy of -7.33 kcal/mole and Ki 4260 nM. Vitexin also exhibits better drug having properties with satisfactory ADMET profiling in relation to Ganetespib.nnnCONCLUSIONnThe result proposes Vitexin to hold prominent antiangiogenic potential surpassing different in silico parameters and thus expected to be a multi-targeted novel antiangiogenic lead.

Chapter 5 - Novel Bioactive Peptides from Cyanobacteria: Functional, Biochemical, and Biomedical Significance

Abstract In the recent years, a number of bioactive peptides and their analogues from cyanobacteria with promising anticancer, antiviral, antibacterial, antifungal, antioxidant, and molluscicidal potentials have been reported. Some of them have even made it into the clinical trials for treatment of cancer and other degenerative diseases. This chapter will focus on some of the significant bioactive peptides and their analogues, biosynthesis, and bioactivity.

Molecular Interaction and Computational Analytical Studies of Pinocembrin for its Antiangiogenic Potential Targeting VEGFR-2: A Persuader of Metastasis

BACKGROUNDnDesigning a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth.nnnOBJECTIVEnThe study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach.nnnMATERIALS AND METHODSnStructures of phytochemicals were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, VEGFR-2 was retrieved from RCSB PDB. Lipinskis rule and ADMET toxicity profiling were carried out on the phytochemicals of the Asteraceae family and the filtered compounds were further promoted for molecular docking and MD simulation analysis. The study extends towards the SOM analysis of Pinocembrin to predict the possible toxic and non-toxic in vivo metabolites via in silico tools (Xenosite Web and PASS online server).nnnRESULTSnThe docking results revealed promising inhibitory potential of Pinocembrin against VEGFR-2 with binding energy of -8.50 kcal/mole as compared to its known inhibitors Sorafenib and YLT192 having binding energy of -6.49 kcal/mole and -8.02 kcal/mol respectively. Further, molecular dynamics (MD) simulations for 10ns were conducted for optimization, flexibility prediction, and determination of folded VEGFR-2 stability. The Hsp90-Pinocembrin complex was found to be quite stable with RMSD value of 0.2nm. Pinocembrin was found to be metabolically stable undergoing phase I metabolism with non-toxic metabolites compared to the standard drug Sorafenib and YLT192.nnnCONCLUSIONnObtained results propose Pinocembrin as a multi-targeted novel lead compound that bears outstanding antiangiogenic potential against VEGFR-2.

Toxic effect of deltamethrin on the life table and development of Helicoverpa armigera (Hubner)

Abstract Effect of deltamethrin (Decis 2.8% EC) on the fitness of Helicoverpa armigera (Hübner) was determined using demographic studies. Survivorship (Ix) and expectancy (ex) was high with commencement of age and gradually decreased with progression of age in the exposed and unexposed groups. Highest number of unhatched eggs (~20%) was recorded with LC50 (79.0 mg/L) opposed to 1% in the control. Daily fecundity rate was significantly greater (200 females/day) in the control than 126 in LC20 (5.13 mg/L). Potential fecundity was lowest (179 females/female/generation) with LC50 treatment than 675 in the control. Smallest value of intrinsic rate of increase (rm) occurred at LC50 (0.0393 females/female/day) while the highest value (0.0539) was at control. Overall larval development was significantly reduced to 18.0 days with LC50 opposed to 24.1 days at control. Pupal period was shortened to 7.6 days with LC50, while it recorded 9.3 days in control.

Hesperidin Induces ROS-Mediated Apoptosis along with Cell Cycle Arrest at G2/M Phase in Human Gall Bladder Carcinoma

Abstract A natural predominant flavonoid hesperidin rich in citrus fruits exhibits multifunctional medicinal properties. The anticancerous potential of hesperidin has been widely explored; however, the gall bladder carcinoma (GBC) still remains untouched due to the unavailability of efficient experimental model. The aim of our study was to identify the apoptotic and antiproliferative potential of hesperidin in GBC. The promising efficacy of hesperidin was assessed through the generation of reactive oxygen species (ROS), cellular apoptosis, and loss of mitochondrial membrane potential (MMP) in the primary cells generated from surgically removed cancerous gall bladder tissues. Moreover, cell cycle analysis and caspases-3 activity were performed to confirm the apoptosis inducing potential of hesperidin. Results revealed that hesperidin exposure for 24u2009h at a dose of 200u2009µM reduced the cell proliferation of GBC cells significantly. In addition, hesperidin treatment further resulted in an increased ROS generation and nuclear condensation at the same dose. Caspase-3 activation and cell cycle arrest at G2/M phase were also accelerated in a dose-dependent manner. Together, these results suggest that hesperidin can be considered as a potential anticancerous compound for the treatment of GBC. Furthermore, evaluation of the pharmacological aspects of hesperidin is desirable for drug development.

Influence of cytokine gene polymorphism on the risk of rheumatic heart disease – A meta-analysis

RHD is an inflammatory disease resulting from interactive immune, genetic, and environmental factors. Various, epidemiological studies have shown the association of genetic variants of cytokine genes with a predisposition to RHD. However, the results from different populations are inconsistent. Therefore, we carried out a meta- analysis of twenty-three published case-control studies and the results indicated that TGF-β1 +869u2009T/C (T vs. C: ORu202f=u202f7.68, 95% CIu202f=u202f1.62-36.50; TTu202f+u202fCT vs. CC ORu202f=u202f1.83, 95%CIu202f=u202f1.39-2.41), TGF-β1-509 (T vs. C: ORu202f=u202f2.76, 95% CIu202f=u202f1.33-5.75), TNF-α(AA vs. GG: ORu202f=u202f4.93,95% CIu202f=u202f2.83-8.58; A vs. G: ORu202f=u202f2.15, 95% CIu202f=u202f1.13-4.12) and IL-1β -511C/T (CCu202f+u202fCT vs. TT: ORu202f=u202f1.35, 95%CIu202f=u202f1.02-1.78;u2009C vs. T: ORu202f=u202f2.36, 95% CIu202f=u202f1.66-3.37) were significantly associated with increased risk of RHD. On the other hand, IL-10(-1082)G/A polymorphism (GA vs. AA: ORu202f=u202f0.91, 95% CIu202f=u202f0.36-2.33; G vs. A: ORu202f=u202f1.90, 95% CIu202f=u202f0.58-6.22) and IL-6-174u202fG/C (CCu202f+u202fGC vs. GG: ORu202f=u202f0.68, 95%CIu202f=u202f0.32-1, C vs. G: ORu202f=u202f1.14, 95% CIu202f=u202f0.82-1.60) were not associated with modified RHD risk. The meta-analysis results were similar in Asians and non-Asians. Therefore, cytokine gene polymorphisms play important role in the genetic susceptibility of RHD in rheumatic fever patients.