Khurshid Ahmad

Immunogenicity of DNA-advanced glycation end product fashioned through glyoxal and arginine in the presence of Fe3+: Its potential role in prompt recognition of diabetes mellitus auto-antibodies

Glyoxal, methylglyoxal and 3-deoxyglucosones are reactive dicarbonyl compounds, which transform free amino groups of proteins and lipoproteins macromolecule into advanced glycation end-products (AGEs). AGEs play a significant role in the pathophysiology of aging and diabetic complications because of their genotoxic effect. Glyoxal also reacts with free amino group of nucleic acids resulting in the formation of DNA-AGEs. The present study reports the genotoxicity and immunogenicity of AGEs formed by Glyoxal-Arginine-Fe(3+) (G-Arg-Fe(3+)) system as a glycating agent. Immunogenicity of native and G-Arg-Fe(3+)-DNA was probed in female rabbits. Immunofluorescence suggests the presence of immune complex deposition in the kidney section of immunized rabbits. Spectroscopic analysis and melting temperature indicates the structural modification in the human DNA. The modified human DNA is found to be highly immunogenic, whereas unmodified form was simply non-immunogenic. This study shows the presence of auto-antibodies against G-Arg-Fe(3+) modified human DNA in the sera of diabetes type 1 and in few cases type 2 patients due to secondary complications of nephropathy. The glyco-oxidative lesions have also been detected in the lymphocyte DNA isolated from patients having type 1 and type 2 diabetes. The results show structural perturbations generating new epitopes in G-Arg-Fe(3+)-DNA rendering it pretty immunogenic.

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.

Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimers disease (AD), Parkinsons disease (PD), Huntingtons disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Structure based molecular inhibition of Caspase-8 for treatment of multi-neurodegenerative diseases using known natural compounds.

Neurodegenerative disorders are often associated with excessive neuronal apoptosis. It is well known that apoptosis is regulated by some intracellular proteases, such as, Caspases (cysteine-dependent, aspartate-specific proteases). In fact, Caspase-8 which is an initiator caspase, has been identified as a key mediator of neuronal apoptosis. In addition, Caspase-8 is found to be coupled with the regulation of various neurodegenerative disorders including Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s Diseases (HD) and Dentatorubral Pallidoluysian Atrophy (DRPLA). Caspase-8 inhibition may provide an effective means of treatment for multiple neurodegenerative disorders. Therefore, the present study describes the molecular interaction of some selected natural compounds with known anti neurodegenerative properties with Caspase-8. Docking between Caspase-8 and each of these compounds (separately) was performed using ‘Autodock4.2’. Out of all the selected compounds, rosmarinic acid and curcumin proved to be the most potent inhibitors of Caspase-8 with binding energy (ΔG) of -7.10 Kcal/mol and -7.08 Kcal/mol, respectively. However, further in vitro and in vivo studies are needed to validate the anti-neurodegenerative potential of these compounds.

Genome-wide comparative analysis of codon usage bias and codon context patterns among cyanobacterial genomes.

With the increasing accumulation of genomic sequence information of prokaryotes, the study of codon usage bias has gained renewed attention. The purpose of this study was to examine codon selection pattern within and across cyanobacterial species belonging to diverse taxonomic orders and habitats. We performed detailed comparative analysis of cyanobacterial genomes with respect to codon bias. Our analysis reflects that in cyanobacterial genomes, A- and/or T-ending codons were used predominantly in the genes whereas G- and/or C-ending codons were largely avoided. Variation in the codon context usage of cyanobacterial genes corresponded to the clustering of cyanobacteria as per their GC content. Analysis of codon adaptation index (CAI) and synonymous codon usage order (SCUO) revealed that majority of genes are associated with low codon bias. Codon selection pattern in cyanobacterial genomes reflected compositional constraints as major influencing factor. It is also identified that although, mutational constraint may play some role in affecting codon usage bias in cyanobacteria, compositional constraint in terms of genomic GC composition coupled with environmental factors affected codon selection pattern in cyanobacterial genomes.

Identification of common therapeutic targets for selected neurodegenerative disorders: An in silico approach

Abstract Neurodegenerative disorders (NDs) are a heterogeneous group of disorders generally characterized by a profound decrease in the size and volume of the human brain due to death of neurons. These disorders include a variety of progressive disorders that result in cognitive and/or motor degradation. The present study was conducted to identify common potential targets for multi-neurodegenerative diseases. To accomplish this, we have selected six common neurodegenerative diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA) for identification of common regulatory target proteins. A total of sixteen common proteins were identified as target proteins by disease pathway analysis and previous studies based on their association with more than two NDs, including AD. An interaction network of each of the sixteen target proteins was then constructed against causative proteins selected from all six NDs by using the STRING 9.1 program. Pathway analysis and the protein–protein interaction network suggested that CASP-3 and CASP-8 were associated with the maximum number of selected NDs and may therefore be the most potent target proteins for treatment of multi-neurodegenerative diseases.

Identification of Potent Caspase-3 Inhibitors for Treatment of Multi- Neurodegenerative Diseases Using Pharmacophore Modeling and Docking Approaches

Neurodegenerative disorders are due to excessive neuronal apoptosis and the caspase-3 plays a key role in the apoptotic pathway. The caspase-3 inhibition may be a validated therapeutic approach for neurodegenerative disorders and an interesting target for molecular modeling studies using both Ligand and structure based approaches. In view of the above we have generated the Ligand based pharmacophore model using the Discovery studio 2.0 software. In addition to this a structure based approach has been used to validate the developed pharmacophoric features to gain a deeper insight into its molecular recognition process. This validated pharmacophore and the docking model was then implemented as a query for pharmacophore based virtual screening to prioritize the probable hits for the Caspase-3. Two ligands, ZINC12405015 and ZINC12405043 were finally selected on the basis of their fit values and docking scores. This study also reveals the important amino acids viz. His-121, Ser-205, Arg-207 which were found to be playing crucial role in the binding of the selected compounds within the active site of caspase-3.

Protease characteristics of bacteriocin producing Lysinibacilli, isolated from fruits and vegetable waste.

This study describes the physical stability and optimization of nutrient components for an extracellular protease produced by Bacillus strains isolated from fruits and vegetable waste, Lucknow, India. The isolated proteases could hydrolyze various native proteinaceous substrates such as bovine serum albumin, casein, skim milk, but not the gelatin. The strain JX416854 and isolate 10 yielded maximum protease (831; 703 U/ml) under optimized conditions: Nutrient, Casein broth; pH 7.0; shaking condition 37°C for 36 h. Crude protease exhibited activity over a wide range of pH (6.0–10.0) and found to be stable at (10–70°C), pH stable at 7- 9.0. The significant protease activity was observed with divalent cations Ca2+ and Mg2+ and EDTA. Further, significant blood destaining properties and stabilities with detergents were also observed. Thus, the significant potency and stability of these enzymes indicated their industrial importance and could be an alternative protease for various industrial applications.

Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte-like cells

Interactions between myoblasts and the surrounding microenvironment led us to explore the role of fibromodulin (FMOD), an extracellular matrix protein, in the maintenance of myoblast stemness and function. Microarray analysis of FMODkd myoblasts and in silico studies were used to identify the top most differentially expressed genes in FMODkd, and helped establish that FMOD‐based regulations of integral membrane protein 2a and clusterin are essential components of the myogenic program. Studies in knockout, obese, and diabetic mouse models helped characterize the operation of a novel FMOD‐based regulatory circuit that controls myoblast switching from a myogenic to a lipid accumulation fate. FMOD regulation of myoblasts is an essential part of the myogenic program, and it offers opportunities for the development of therapeutics for the treatment of different muscle diseases.—Lee, E. J., Jan, A. T., Baig, M. H., Ahmad, K., Malik, A., Rabbani, G., Kim, T., Lee, I.‐K., Lee, Y. H., Park, S.‐Y., Choi, I. Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte‐like cells. FASEB J. 32, 768–781 (2018). www.fasebj.org

Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An in Silico-updated Overview

BACKGROUND Alzheimers disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinsons disease (PD), Amyotrophic lateral sclerosis (ALS), Huntingtons disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies. METHOD In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation. CONCLUSION The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.