Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the... more
Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the decision process and patterns. This can create difficulties in understanding and making sense of the outputs of algorithms used in drug discovery. Therefore, using explainable AI (XAI) techniques, the causes and consequences of the decision process are better understood. This can help further improve the drug discovery process and make the right decisions. To address this issue, Explainable Artificial Intelligence (XAI) emerged as a process and method that securely captures the results and outputs of machine learning (ML) and deep learning (DL) algorithms. Using techniques such as SHAP (SHApley Additive ExPlanations) and LIME (Locally Interpretable Model‐Independent Explanations) has made the drug targeting phase clearer and more understandable. XAI methods are expected to reduce time and cost in future computational drug discovery studies. This review provides a comprehensive overview of XAI‐based drug discovery and development prediction. XAI mechanisms to increase confidence in AI and modeling methods. The limitations and future directions of XAI in drug discovery are also discussed.
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Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the... more
Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the decision process and patterns. This can create difficulties in understanding and making sense of the outputs of algorithms used in drug discovery. Therefore, using explainable AI (XAI) techniques, the causes and consequences of the decision process are better understood. This can help further improve the drug discovery process and make the right decisions. To address this issue, Explainable Artificial Intelligence (XAI) emerged as a process and method that securely captures the results and outputs of machine learning (ML) and deep learning (DL) algorithms. Using techniques such as SHAP (SHApley Additive ExPlanations) and LIME (Locally Interpretable Model‐Independent Explanations) has made the drug targeting phase clearer and more understandable. XA...
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Human cytomegalovirus (HCMV) poses a serious public health problem causing morbidity and mortality in transplant recipients, immunocompromised patients, and congenitally infected newborns. Considering the recent reports of emergence of... more
Human cytomegalovirus (HCMV) poses a serious public health problem causing morbidity and mortality in transplant recipients, immunocompromised patients, and congenitally infected newborns. Considering the recent reports of emergence of Ganciclovir drug resistance, vaccine development is the need of an hour. In the present study, a multi-epitope vaccine was constructed targeting the major hotspot- the pentavalent complex of glycoproteins (H/L/UL128-UL130-UL131) of HCMV, and other important target proteins- gB and pp65. The vaccine designed was composed of series of epitopes belonging to CD4, CD8 and B cells. As an immunobooster, the CpG motifs was linked to the vaccine which severed as an adjuvant. The affinity, stability and flexibility of the vaccine construct with the immune receptor- Toll like receptor -9 (TLR-9) was investigated by molecular docking and molecular dynamics simulations. The in-silico immune simulations of the vaccine sequence were also carried out to determine its ability to stimulate different immune components. Further, an in-silico cloning of the vaccine construct was performed to analyze the feasibility of its expression and translation efficiency in pET-28a (+) vector. The overall results obtained indicated the vaccine to be immunogenic, non-allergic, had high population coverage, high affinity and stability with the immune receptor, had efficient expression in host E. coli and was effective in stimulating different immune cell types like T helper, T cytotoxic, B cells, dendritic cells, macrophages and interleukins. The proposed vaccine construct is expected to be highly efficacious and needs to be carried forward by the vaccinologists to test its efficacy in lab settings.
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Hantaviruses are negative-sense, enveloped, single-stranded RNA viruses of the family Hantaviridae. In recent years, rodent-borne hantaviruses have emerged as novel zoonotic viruses posing a substantial health issue and socioeconomic... more
Hantaviruses are negative-sense, enveloped, single-stranded RNA viruses of the family Hantaviridae. In recent years, rodent-borne hantaviruses have emerged as novel zoonotic viruses posing a substantial health issue and socioeconomic burden. In the current research, a reverse vaccinology approach was applied to design a multi-epitope-based vaccine against hantavirus. A set of 340 experimentally reported epitopes were retrieved from Virus Pathogen Database and Analysis Resource (ViPR) and subjected to different analyses such as antigenicity, allergenicity, solubility, IFN gamma, toxicity, and virulent checks. Finally, 10 epitopes which cleared all the filters used were linked with each other through specific GPGPG linkers to construct a multi-antigenic epitope vaccine. The designed vaccine was then joined to three different adjuvants—TLR4-agonist adjuvant, β-defensin, and 50S ribosomal protein L7/L12—using an EAAAK linker to boost up immune-stimulating responses and check the potency...
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This study aims to determine UV-B resistance and to investigate computational analysis and antioxidant potential of methoxy-flavones of Micromonospora aurantiaca TMC-15 isolated from Thal Desert, Pakistan. The cellular extract was... more
This study aims to determine UV-B resistance and to investigate computational analysis and antioxidant potential of methoxy-flavones of Micromonospora aurantiaca TMC-15 isolated from Thal Desert, Pakistan. The cellular extract was purified through solid phase extraction and UV-Vis spectrum analysis indicated absorption peaks at λmax 250 nm, 343 nm, and 380 nm that revealed the presence of methoxy-flavones named eupatilin and 5-hydroxyauranetin. The flavones were evaluated for their antioxidant as well as protein and lipid peroxidation inhibition potential using di(phenyl)-(2,4,6-trinitrophenyl) iminoazanium (DPPH), 2,4-dinitrophenyl hydrazine (DNPH), and thiobarbituric acid reactive substances (TBARS) assays, respectively. The methoxy-flavones were further studied for their docking affinity and interaction dynamics to determine their structural and energetic properties at atomic level. The antioxidant potential, protein and lipid oxidation inhibition and DNA damage preventive abilit...
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Background: Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limits its therapeutic application.... more
Background: Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limits its therapeutic application. Objectives: The present study aimed at developing a nanoliposomal carrier system for B. amplexicaulis extracts for improved cellular uptake, thus resulting in enhanced anticancer activity. Methods: Ultra Pressure Liquid Chromatography (UPLC) was used to identify major compounds in the plant extract. Nanoliposomes (NLs) were prepared by employing a thin-film rehydration method using DPPC, PEG2000DSPE and cholesterol, followed by characterization through several parameters. In vitro screening was performed against breast cancer cell line (MCF-7) and Hepatocellular carcinoma cell line (HepG-2) using MTT-assay. Raw extract and nanoliposomes were tested on Human Umbilical Vein Endothelial Cells (HUVEC). Moreover, molecular docking was performed to valid...
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Among cancers, prostate cancer (PCa) is frequently detected solid tumor and a growing problem for the male population, globally. Newer treatment modalities with specific targets are required for management. Plant-derived agents/drugs have... more
Among cancers, prostate cancer (PCa) is frequently detected solid tumor and a growing problem for the male population, globally. Newer treatment modalities with specific targets are required for management. Plant-derived agents/drugs have historically been useful in cancer therapeutics. Natural metabolite i.e. plectranthoic acid (PA), inhibits the proliferation of PCa cells and has potent anti-cancer potential. Herein, we aim to identify the molecular signatures of PA. Proteins from control and PA-treated PCa cells were analysed using high-throughput labeled free proteomics approach. Data was processed with the SIEVE software and thoroughly analysed by using Ingenuity pathway analysis (IPA) and PANTHER. A total of 98 unique peptides, showing >2 fold change, were identified. Results indicated that PA modulates oncogenic pro-survival and pro-apoptotic signaling pathways in PCa cells. mTOR was the major canonical pathway targeted by PA, the inhibition of which was likely to induce P...
Research Interests: Proteomics and Medicine
BACKGROUND Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limit their therapeutic application.... more
BACKGROUND Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limit their therapeutic application. OBJECTIVES The present study was aimed at developing a nanoliposomal carrier system for B. amplexicaulis extracts for its improved cellular uptake thus resulting in enhanced anticancer activity. METHODS Ultra Pressure Liquid Chromatography (UPLC) was used to identify major compounds in the plant extract. Nanoliposomes (NLs) were prepared using a thin-film rehydration method using DPPC, PEG2000DSPE and cholesterol, followed by characterization through several parameters. In vitro screening was performed against breast cancer cell line (MCF-7) and Hepatocellular carcinoma cell line (HepG-2) using MTT-assay. Raw extract and nanoliposomes were tested on Human Umbilical Vein Endothelial Cells (HUVEC). Moreover, molecular docking was performed to validat...
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Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging health concern due to its high mortality rate of 35%. At present, no vaccine is available to protect against MERS-CoV infections. Therefore, an in silico search for... more
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging health concern due to its high mortality rate of 35%. At present, no vaccine is available to protect against MERS-CoV infections. Therefore, an in silico search for potential antigenic epitopes in the non-redundant proteome of MERS-CoV was performed herein. First, a subtractive proteome-based approach was employed to look for the surface exposed and host non-homologous proteins. Following, immunoinformatics analysis was performed to predict antigenic B and T cell epitopes that were used in the design of a multi-epitopes peptide. Molecular docking study was carried out to predict vaccine construct affinity of binding to Toll-like receptor 3 (TLR3) and understand its binding conformation to extract ideas about its processing by the host immune system. We identified membrane protein, envelope small membrane protein, non-structural protein ORF3, non-structural protein ORF5, and spike glycoprotein as potential candida...
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Leber congenital amaurosis (LCA) is a rare form of early onset vision loss or blindness due to retinal dystrophy. This condition is characterized by early vision loss, nystagmus and severe retinal dysfunction. To date, genetic studies... more
Leber congenital amaurosis (LCA) is a rare form of early onset vision loss or blindness due to retinal dystrophy. This condition is characterized by early vision loss, nystagmus and severe retinal dysfunction. To date, genetic studies have reported 19 genes to be associated with autosomal recessive LCA, most of which are involved in the retinal morphology and the physiology of the phototransduction pathway. In the current study, a large consanguineous family segregating congenital blindness was ascertained from the Dera Ismail Khan region of Pakistan. Genetic analysis was performed through genomewide SNP genotyping (for homozygosity-by-descent mapping), whole-exome sequencing (for mutation identification) and Sanger sequencing (for segregation analysis). In silico structural predictions were performed through SWISS-Model (structure prediction) and ClusPro (molecular docking). Molecular investigation of the present LCA family identified a novel homozygous missense mutation p.Asp306Val in GUCY2D gene (NM_000180.3:c.917A>T). In silico structural modelling and interaction studies predicted significant changes in protein folding and interacting residues. The present molecular genetic study further extends the mutational spectrum of GUCY2D in LCA, and its genetic heterogeneity in the Pakistani population. The findings of the computational studies on protein structure and interaction profile predicted pathogenic consequences of p.Asp306Val on GUCY2D function.
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Proline dehydrogenase is an important mitochondrial enzyme that is encoded by the PRODH gene. Biologically, a mutation in this gene affects the activity of proline dehydrogenase enzyme that is normally involved in conversion of proline to... more
Proline dehydrogenase is an important mitochondrial enzyme that is encoded by the PRODH gene. Biologically, a mutation in this gene affects the activity of proline dehydrogenase enzyme that is normally involved in conversion of proline to glutamate. However, its reduced or null activity leads to excess quantity of proline in the body, which results in different psychiatric phenotypes along with intellectual disability. In the present study, we performed in silico analysis on all reported mutations of PRODH. The 3D models of normal and mutant PRODH were predicted using I-TASSER. The predicted structures were visualized and superimposed using chimera 1.13.1. The CASTp was used to identify active sites in modelled proteins. Protein-protein docking was done with Cluspro, while protein-substrate docking was done with Auto Dock 1.5.6 and-MGL tools and the results were visualized using LigPlus+ v.2.2 and Discovery studio 2020 respectively. Alignment of 3D models (mutant with wildtype) reve...
V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for... more
V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA ac...
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Hepatitis C virus (HCV) causes chronic and acute hepatitis infections. As there is extreme variability in the HCV genome, no approved HCV vaccine has been available so far. An effective polypeptide vaccine based on the functionally... more
Hepatitis C virus (HCV) causes chronic and acute hepatitis infections. As there is extreme variability in the HCV genome, no approved HCV vaccine has been available so far. An effective polypeptide vaccine based on the functionally conserved epitopes will be greatly helpful in curing disease. For this purpose, an immuno-informatics study is performed based on the published HCV subtype-3a from Pakistan. First, the virus genome was translated to a polyprotein followed by a subsequent prediction of T-cell epitopes. Non-allergenic, IFN-γ producer, and antigenic epitopes were shortlisted, including 5 HTL epitopes and 4 CTL, which were linked to the final vaccine by GPGPG and AAY linkers, respectively. Beta defensin was included as an adjuvant through the EAAAK linker to improve the immunogenicity of the polypeptide. To ensure its safety and immunogenicity profile, antigenicity, allergenicity, and various physiochemical attributes of the polypeptide were evaluated. Molecular docking was c...
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Crimean-Congo hemorrhagic fever (CCHF) is a highly severe and virulent viral disease of zoonotic origin, caused by a tick-born CCHF virus (CCHFV). The virus is endemic in many countries and has a mortality rate between 10% and 40%. As... more
Crimean-Congo hemorrhagic fever (CCHF) is a highly severe and virulent viral disease of zoonotic origin, caused by a tick-born CCHF virus (CCHFV). The virus is endemic in many countries and has a mortality rate between 10% and 40%. As there is no licensed vaccine or therapeutic options available to treat CCHF, the present study was designed to focus on application of modern computational approaches to propose a multi-epitope vaccine (MEV) expressing antigenic determinants prioritized from the CCHFV genome. Integrated computational analyses revealed the presence of 9 immunodominant epitopes from Nucleoprotein (N), RNA dependent RNA polymerase (RdRp), Glycoprotein N (Gn/G2), and Glycoprotein C (Gc/G1). Together these epitopes were observed to cover 99.74% of the world populations. The epitopes demonstrated excellent binding affinity for the B- and T-cell reference set of alleles, the high antigenic potential, non-allergenic nature, excellent solubility, zero percent toxicity and inter...
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Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030.... more
Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dosespecific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territori...
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With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as... more
With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of −9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of −10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to...
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SARS-CoV2 has affected millions of people around the globe with hundreds of mortalities. The emergence of SARS-COV2 is very recent, and there is no potential drug or vaccine available. In this review, we have compiled the most frequently... more
SARS-CoV2 has affected millions of people around the globe with hundreds of mortalities. The emergence of SARS-COV2 is very recent, and there is no potential drug or vaccine available. In this review, we have compiled the most frequently used computational methods in drug discovery, target proteins of SARS-CoV2 as well as implementation of computational methods. Most recent literature on SARS-CoV2 has been compiled from various journal search engines including Google Scholar, Academia, PubMed, Scopus, Research Gate, and the Web of Science. The keywords chosen for the searches were COVID-19, Corona Virus, SARS-CoV2, drug development and future directions. This review has far reaching implications to both the public health and pharmaceutical industries for potential novel drug development against SARS-CoV2.
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The death toll and the total number of infected individuals due to the ongoing pandemic of SARS-CoV-2 infection have exceeded that of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) as the disease has... more
The death toll and the total number of infected individuals due to the ongoing pandemic of SARS-CoV-2 infection have exceeded that of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) as the disease has raged around the world. So far the global efforts to tackle COVID-19 include the launch of Sputnik V vaccine by Russia, 42 vaccines presently undergoing clinical trials on humans and around 92 vaccines under preclinical active investigation in animals. Majority of the SARS-CoV-2 infected individuals have been reported to show mild symptoms whereas a considerable number show no symptoms at all. SARS-CoV-2 is believed to spread from infected individuals who are asymptomatic in addition to the symptomatic individuals. In this review we discussed how the mildly infected and asymptomatic individuals raise serious concerns and complicate the processes of screening, detection, quarantine, tracking and treatmentthatareinpracticetopreventthetransmissionofthe...
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Abstract d -Alanine- d -alanine ligase (Ddl), an enzyme that catalyzes the d -ala- d -ala dipeptide formation in UDPMurNAc pentapeptide, is a part of peptidoglycan biosynthesis machinery. Inhibition of enzyme leads to bacterial growth... more
Abstract d -Alanine- d -alanine ligase (Ddl), an enzyme that catalyzes the d -ala- d -ala dipeptide formation in UDPMurNAc pentapeptide, is a part of peptidoglycan biosynthesis machinery. Inhibition of enzyme leads to bacterial growth arrest making it a viable and attractive target for screening of potent antibacterial drugs. Combination of virtual screening, molecular docking, in silico pharmacokinetics, molecular dynamics (MD) simulation, and binding free energy calculations based on Molecular Mechanics Generalized Born and Surface Area (MMGBSA) and WaterSwap were applied in the current framework for the detailed analysis of potent natural inhibitors against Ddl enzyme. Comparative molecular docking supported with computational druglikeness revealed compound-331 (6-(4-((3-methoxyphenylsulfonamido) methyl) phenyl)-2-methylnicotinamide) as the best docked inhibitor. The inhibitor has Genetic Optimization for Ligand Docking (GOLD) fitness score of 84.2 and AutoDock Vina binding energy of −7.2 kcal/mol. The inhibitor exhibited to have a better druglikeness by adhering to Lipinski rule of five, Ghose rule, Veber filter, Egan filter, and Muegge filter in contrast to d -cycloserine, which violates Ghose and Muegge rule. MD simulation unravels that in complex over the course of 100-ns, the enzyme remained highly stable with mean Root Mean Square Deviation (RMSD) of 1.4 A when compared to an undocked structure having RMSD of 1.6 A. Root Mean Square Fluctuation (RMSF) predicted stable behaviour of the active site residues in both undocked and docked system with average RMSD values of 1.2 A and 0.7 A, respectively. Radial Distribution Function (RDF) and Axial Frequency Distribution (AFD) demonstrated Lys176 and Trp177 as critical residues of enzyme for binding, anchoring and bridging strong hydrogen and hydrophobic contacts between enzyme and the inhibitor. The estimated MMGBSA based binding free energy for the complex is −47.36 kcal/mol, signifying its stable nature. WaterSwap further indicated a worthy agreement on the affinity of inhibitor towards enzyme active pocket. This newly discovered natural inhibitor might serve a parent structure for the development of more potent derivatives with encouraging biological activity.
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skin aging, manifested as wrinkles, age spots and elasticity degradation. In ultraviolet radiated areas degradation of the collagen results in skin aging 5 because of matrix metalloproteinases (MMPs). These are secreted from dermal... more
skin aging, manifested as wrinkles, age spots and elasticity degradation. In ultraviolet radiated areas degradation of the collagen results in skin aging 5 because of matrix metalloproteinases (MMPs). These are secreted from dermal fibroblasts and epidermal keratinocytes in response to ultraviolet (UV) radiations. The MMPs activation is the result of secretion of number of cytokines by reactive oxygen 6,7 species in keratinocytes. Oxidative stress also results in formation of different degraded and unstable products like toxic aldehydes and ketones, protein oxidation and DNA mutations. All these results in different pathological conditions in host cells and ultimately leads to premature aging and cancer. The suppression of inflammatory cytokines and inhibition of MMPs is crucial for preventing age 8 related skin deterioration. The matrix metalloproteinase group consist of metzincin super family which comprises of over 20 9,10 different zinc peptidases. This series of enzymes Introdu...
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Collagen is the single most abundant protein in the extracellular matrix in the animal kingdom, with remarkable structural and functional diversity and regarded one of the most useful biomaterials. Etymologically, the term collagen comes... more
Collagen is the single most abundant protein in the extracellular matrix in the animal kingdom, with remarkable structural and functional diversity and regarded one of the most useful biomaterials. Etymologically, the term collagen comes from Greek kola 'glue' and gen 'giving birth to'. Thus, it is not surprising that the various collagens and the structures they form all serve the same purpose, to help tissues withstand stretching. Among the functions the various collagens are involved in are cell adhesion and migration, tissue repair, scaffolding and morphogenesis. Thus knowledge about the structure and properties of collagen, how they change depending on the nature of the local environment as well as the nature and specificity of collagen interactions with its partners is central to discerning the role of collagen in medical applications such as imaging, drug delivery and tissue engineering, and in the design and construction of synthetic collagen-like materials f...
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α-Methylacyl-CoA racemase (AMACR) has recently been reported as a vital solid tumor marker and is an attractive target for designing anti-tumor agents. It is a mitochondrial and peroxisomal enzyme which plays a central role in the... more
α-Methylacyl-CoA racemase (AMACR) has recently been reported as a vital solid tumor marker and is an attractive target for designing anti-tumor agents. It is a mitochondrial and peroxisomal enzyme which plays a central role in the oxidation of cholesterol metabolites and branched chain fatty acids. The three dimensional structure of human AMACR is still unknown. In the current study, homology model using Modeller and different modelling servers based on 1X74A as template is reported. The three dimensional model generated was validated and evaluated using various available programs like PROCHECK, ERRAT, ProSA energy plots, etc. In order to find potent inhibitors of AMACR, a docking study using compounds reported to be active against this enzyme of other organisms was conducted. Among the studied inhibitors, 2-methylmyristoyl- CoA effectively binds to and inhibits the enzyme by means of hydrogen bond interactions with the key residues of pocket. Moreover, molecular dynamics simulation was carried out to check the stability of AMACR/2-methylmyristoyl-CoA complex. The results illustrated the ligand's high binding affinity with enzyme and the stability of hydrogen bond interactions in dynamic condition. Hence, 2-methylmyristoyl-CoA has been suggested to be a promising lead compound for the design of new inhibitors against AMACR.
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β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and... more
β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7Å and 1.6Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become a lead compound.
Research Interests: Molecular Dynamics Simulation, Protein Stability, Computer Software, Sequence alignment, Drug Design, and 11 moreMolecular docking, Protein Secondary Structure Prediction, THEORETICAL AND COMPUTATIONAL CHEMISTRY, Protein Conformation, Amino Acid Sequence, Protein Binding, Biochemistry and cell biology, Molecular Structure, Dimerization, Molecular Sequence Data, and binding sites
In the current study, identification of new potent small inhibitors of human lysosomal acid lipase using structure-based methods has been reported. Virtual Screening (VS), compounds from literature and molecular docking studies were... more
In the current study, identification of new potent small inhibitors of human lysosomal acid lipase using structure-based methods has been reported. Virtual Screening (VS), compounds from literature and molecular docking studies were employed to find the suitable inhibitors against lysosomal acid lipase (LAL). Specifically for this study a homology model of LipA enzyme was generated based on the structure of dog gastric lipase. As a result of structurebased virtual screening 28 inhibitors were identified from ZINC database. Rest of the inhibitors were selected from literature. Among the studied 65 inhibitors, compound having zinc ID ZINC15707335 exhibiting minimum binding affinity and hydrogen bond and hydrophobic interactions with specific amino acid residues was selected as lead compound.
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... disease Sumra Wajid Abbasi Saima Kulsoom Naveeda Riaz ... BuChE/BChE Butyrylcholinesterase ACh Acetylcholine BChEIs Butyrylcholinesterase inhibitors HBD Hydrogen-bond donors HBA Hydrogen-bond accepters HY Hydrophobic AR Aromatic... more
... disease Sumra Wajid Abbasi Saima Kulsoom Naveeda Riaz ... BuChE/BChE Butyrylcholinesterase ACh Acetylcholine BChEIs Butyrylcholinesterase inhibitors HBD Hydrogen-bond donors HBA Hydrogen-bond accepters HY Hydrophobic AR Aromatic ring VMD Visual ...
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ABSTRACT Homology modeling in combination with molecular docking studies has been applied to predict the binding modes of the Hepatitis C virus (HCV) NS5B-3a inhibitors within the pocket of NS5B polymerase of HCV genotype 3a. Structure... more
ABSTRACT Homology modeling in combination with molecular docking studies has been applied to predict the binding modes of the Hepatitis C virus (HCV) NS5B-3a inhibitors within the pocket of NS5B polymerase of HCV genotype 3a. Structure modeling and docking using Genetic Optimization for Ligand Docking (GOLD) were carried out to understand the ligand binding properties of NS5B-3a and to identify a potent inhibitor against it. The three-dimensional homology model of Pakistani strain is not available and was built based on the HCV-J4 NS5B polymerase structure. Compound 1 possessing high GOLD fitness score of 62.17 with IC50 value of 0.04 μM was selected as the potent inhibitor. The docking analysis depicted that hydrogen bonding, ionic and hydrophobic interactions contributed significantly for its ligand binding and the amino acid residues Arg442 and His403 seemed to be the anchor residues for receptor recognition. For developing a connection between the experimental bioactivities and GOLD fitness scores, a squared correlation coefficient was calculated and found as acceptable with the value of r 2 = 0.67. These findings may act as potent lead in designing effective NS5B-3a inhibitors.
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... disease Sumra Wajid Abbasi Saima Kulsoom Naveeda Riaz ... BuChE/BChE Butyrylcholinesterase ACh Acetylcholine BChEIs Butyrylcholinesterase inhibitors HBD Hydrogen-bond donors HBA Hydrogen-bond accepters HY Hydrophobic AR Aromatic... more
... disease Sumra Wajid Abbasi Saima Kulsoom Naveeda Riaz ... BuChE/BChE Butyrylcholinesterase ACh Acetylcholine BChEIs Butyrylcholinesterase inhibitors HBD Hydrogen-bond donors HBA Hydrogen-bond accepters HY Hydrophobic AR Aromatic ring VMD Visual ...
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ABSTRACT d-Alanine:d-alanine ligase (Ddl) catalyzes the ATP-driven ligation of two d-alanine (d-Ala) molecules resulting in the formation of d-alanyl:d-alanine dipeptide. Inhibition of Ddl prevents bacterial growth, which makes this... more
ABSTRACT d-Alanine:d-alanine ligase (Ddl) catalyzes the ATP-driven ligation of two d-alanine (d-Ala) molecules resulting in the formation of d-alanyl:d-alanine dipeptide. Inhibition of Ddl prevents bacterial growth, which makes this enzyme an attractive and viable target for searching effective antimicrobial drugs. Current study aimed at the discovery of potent inhibitors against Strepotococcus sanguinis SK36 Ddl (SsDdl). Using comparative molecular modeling approach, models for SsDdl were constructed by MODELLER and other web servers. The model with best stereo-chemical profile was further studied for structure function relationship by performing docking with seventy nine inhibitors. The results demonstrated the model generated via MODELLER was the best among all predicted SsDdl structures. Docking analysis revealed that compounds 73 and 61, obtained from pyridopyrimidine scaffolds yielded highest GOLD scores and exhibited consistently better binding interactions. The final compounds exhibit reasonable SsDdl inhibitory activity and can be further employed to design derivatives with customized activities.