Usman Mirza- PhD, Pharmaceutical Sciences
- PostDoc Position at University of Windsor
Usman Mirza
- PhD, Pharmaceutical Sciences
- PostDoc Position at University of Windsor
Computational Chemist: Therapeutic Targets and Computational Approaches on Drug Design and Development.
About
73
Publications
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Introduction
I am applying computational methods to biological systems. My inter-disciplinary research focuses on cell signalling pathways, protein modelling and dynamics, investigation of molecular mechanisms of protein/drug and protein/protein interactions by ligand-based (QSAR, similarity and pharmacophore searches) and structure based methods (docking, virtual screening, de-novo design) and lead optimization of biologically active compounds having good pharmacological properties.
Current institution
Additional affiliations
January 2021 - present
Position
- PostDoc Position
Description
- My prime research involves computer-aided drug design, particularly hit-to-lead optimization.
October 2016 - October 2020
September 2012 - October 2016
Education
February 2010 - March 2012
Publications
Publications (73)
The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify par...
The recent outbreak of Zika virus (ZIKV) infection in Brazil has developed to a global health concern due to its likely association with birth defects (primary microcephaly) and neurological complications. Consequently, there is an urgent need to develop a vaccine to prevent or a medicine to treat the infection. In this study, immunoinformatics app...
Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin–melanocortin pathway in controlling energy balance, appetite and body weight¹. The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin–melanocortin signaling. These genes...
Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11500 deaths according to a recent 2018 WHO report. With mortality rates up to 90 %, it is nowadays one of the most deadly infectious diseases. However, no FDA approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fata...
The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear and has threatened global health security. Although phenomenal efforts are in progress to effectively combat this COVID-19 outbreak. Still, no licensed antiviral drugs or v...
The emergence of drug-resistance-inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 1...
The emergence of drug resistance inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 1...
Background
Intellectual disability (ID) is a condition that varies widely in both its clinical presentation and its genetic underpinnings. It significantly impacts patients’ learning capacities and lowers their IQ below 70. The solute carrier (SLC) family is the most abundant class of transmembrane transporters and is responsible for the translocat...
Introduction:
Besides human leukocyte antigen (HLA-DRB1) locus, more than 100 loci across the genome have been identified and linked with the onset, expression and/or progression of rheumatoid arthritis (RA). However, there are still grey areas in our understanding of the key genetic contributors of the disease, particularly in familial cases.
Me...
Introduction
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70.
Methods
The current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmen...
Despite advanced diagnosis and detection technologies, prostate cancer (PCa) is the most prevalent neoplasms in males. Dysregulation of the androgen receptor (AR) is centrally involved in the tumorigenesis of PCa cells. Acquisition of drug resistance due to modifications in AR leads to therapeutic failure and relapse in PCa. An overhaul of comprehe...
We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carried pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity, using an inhouse computational staged approach. This included analysis of whole-exome sequencin...
Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low toxicity. Although noncanonical residues can always be used, employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico screening. Towards this goal, t...
Crimean–Congo haemorrhagic fever (CCHF), caused by Crimean–Congo haemorrhagic fever virus (CCHFV), is a disease of worldwide importance (endemic yet not limited to Asia, Middle East, and Africa) and has triggered several outbreaks amounting to a case fatality rate of 10–40% as per the World Health Organization. Genetic diversity and phylogenetic da...
The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC...
Rift valley fever virus (RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp; L protein) of the R...
Processive cellulase CelO is an important modular enzyme of C. thermocellum. To study the effect of carbohydrate binding module (CBM3b) on catalytic domain of CelO (GH5), four engineered derivatives of CelO were designed by truncation and terminal fusion of CBM3b. These are CBM at N‐terminus, native form (CelO‐BC, 62 kDa); catalytic domain only (Ce...
With expanding recent outbreaks and a lack of treatment options, the Zika virus (ZIKV) poses a severe health concern. The availability of ZIKV NS2B-NS3 co-crystallized structures paved the way for rational drug discovery. A computer-aided structure-based approach was used to screen a diverse library of compounds against ZIKV NS2B-NS3 protease. The...
A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the re...
The U.S. National Research Council (NRC) introduced new approaches to report toxicity studies. The NRC vision is to explore the toxicity pathways leading to the adverse effects in intact organisms by the exposure of the chemicals. This study examines the toxicity profiling of the naphthalene-2-yl 2-chloro-5-dinitrobenzoate (SF5) by adopting the vis...
Cholera is a severe small intestine bacterial disease caused by consumption of water and food contaminated with Vibrio cholera. The disease causes watery diarrhea leading to severe dehydration and even death if left untreated. In the past few decades, V. cholerae has emerged as multidrug-resistant enteric pathogen due to its rapid ability to adapt...
Phytochromes (Phys) are known as red/far-red light photoreceptors and are responsible for directing the photosensory responses across the species, majorly from fungal, bacterial and plant kingdoms. Such responses majorly include photosynthetic potential and pigmentation in bacteria, whereas in a plant, they are involved in chloroplast development a...
3CLpro is essential for SARS‐CoV‐2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography‐guided fragment‐based drug discovery approach was employed to design new inhibitors for SARS‐CoV‐2 3CLpro. All small molecules co‐crystallized with SARS‐CoV‐2 3CLpro w...
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 focu...
Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using...
Phytochromes (Phys) are known as red/far-red light photoreceptors and are responsible for directing the photosensory responses across the species, majorly from fungal, bacterial and plant kingdoms. Such responses majorly include photosynthetic potential and pigmentation in bacteria, whereas in a plant, they are involved in chloroplast development a...
The presented study was designed to probe the toxicity potential of newly identified compound naphthalen-2-yl 3,5-dinitrobenzoate (SF1). Acute, subacute toxicity and teratogenicity studies were performed as per Organization of economic cooperation and development (OECD) 425, 407, and 414 test guidelines, respectively. An oral dose of 2000 mg/kg to...
Toxicity studies are necessary for the development of a new drug. Naphthalene is a bicyclic molecule and is easy to derivatize. In our previous study, a derivative of naphthalene (4-phenyl,3,4-dihydrobenzoquinoline-2(H)one) was synthesized and reported its in vitro activity on different enzymes. This study was a probe to investigate the toxicity po...
Staphylococcus aureus is a deadly human bacterial pathogen that causes a wide variety of clinical manifestations. Invasive S. aureus infections in hospitals and the community are one of the main causes of mortality and morbidity, as virulent and multi-drug-resistant strains have evolved. There is an unmet and urgent clinical need for immune-based n...
Ifosfamide is a widely used chemotherapeutic agent having broad-spectrum efficacy against several tumors. However, nephro, hepato, neuro cardio, and hematological toxicities associated with ifosfamide render its use limited. These side effects could range from organ failure to life-threatening situations. The present study aimed to evaluate the att...
p>3CLpro is a vital protein for the SARS-CoV-2 replications and its inhibition using small molecules is a bona fide approach used to develop new drugs against the virus. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. Protein Data Bank was expl...
Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of ho...
Simple Summary
COVID-19, caused by a novel coronavirus, SARS-CoV-2, first emerged in China in December 2019, and then spread around the globe with more than 29 million confirmed infections. Immunoinformatics and molecular modelling techniques are time-efficient methods that are used to accelerate the discovery and design of the candidate peptides f...
The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the World Health Organization has declared it a pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. The urgency of the situation requires t...
Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly...
Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often...
The papain-like protease (PLpro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics...
Cellulases are a set of lignocellulolytic enzymes, capable of producing eco-friendly low-cost renewable bioethanol. However, low stability and hydrolytic activity limit their wide-scale applicability at the industrial scale. In this work, we report the domain engineering of endoglucanase (cel6A) of Thermobifida fusca to improve their catalytic acti...
Withania coagulans (W. coagulans) is well-known in herbal medicinal systems for its high biological potential. Different parts of the plant are used against insomnia, liver complications, asthma, and biliousness, as well as it is reported to be sedative, emetic, diuretic, antidiabetic antimicrobial, anti-inflammatory, antitumor, hepatoprotective, a...
The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of...
Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleoti...
The ubiquitin-specific protease 2 (USP) belongs to the family of deubiquitinases and plays a critical role in tumors cells’ survival and therefore signifies an important therapeutic target. Previous studies have indicated promising efficacies of potent human USP2 inhibitors including, thiopurine analogues against SARS-CoV papain-like proteases (PLp...
The recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health security. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are underway to test possible therapies. During this urgency situation,...
The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the world health organization declared it pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. In this urgency situation, development of SAR...
The present study explored phytochemicals, porcine pancreatic α-amylase (PPA) and lipase (PPL) inhibitory activities and antioxidant potential of polar and nonpolar extracts of the leaves and flowers of Ocimum basilicum and the in-silico mode of interaction between these enzymes and the major chemical constituents of the herb. The hexane extract (H...
The present study explored phytochemicals, porcine pancreatic α-amylase (PPA) and lipase (PPL) inhibitory activities and antioxidant potential of polar and nonpolar extracts of the leaves and flowers of Ocimum basilicum and the in-silico mode of interaction between these enzymes and the major chemical constituents of the herb. The hexane extract (H...
The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypod...
Background:
Jalili syndrome (JS) is a rare cone-rod dystrophy (CRD) associated with amelogenesis imperfecta (AI). The first clinical presentation of JS patients was published in 1988 by Jalili and Smith. Pathogenic mutations in the Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4 (CNNM4) magnesium transporter protein have been repo...
Members of genus Pteris have their established role in the traditional herbal medicine system. In the pursuit to identify its biologically active constituents, the specie Pteris cretica L. (P. cretica) was selected for the bioassay-guided isolation. Two new maleates (F9 and CB18) were identified from the chloroform extract and the structures of the...
Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontain-ment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here,...
Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to qu...
The Crimean-Congo Hemorrhagic Fever virus (CCHFV) is a segmented negative single-stranded RNA virus (−ssRNA) which causes severe hemorrhagic fever in humans with a mortality rate of ~50%. To date, no vaccine has been approved. Treatment is limited to supportive care with few investigational drugs in practice. Previous studies have identified viral...
The disulfide bond signal sequence (DsbAss) protein is characterized as an important virulence factor in gram-negative bacteria. This study aimed to analyze the “alanine” alteration in the hydrophobic (H) region of DsbAss and to understand the conformational DsbAss alteration(s) inside the fifty-four homolog (Ffh)-binding groove which were revealed...
Tumorigenesis in humans is a multistep progression that imitates genetic changes leading to cell transformation and malignancy. Oncogenic kinases play a central role in cancer progression, rendering them putative targets for the design of anti-cancer drugs. The presented work aims to identify the potential multi-target inhibitors of oncogenic recep...
Human papillomavirus (HPV) induced cervical cancer is the second most common cause of death, after breast cancer, in females. Three prophylactic vaccines by Merck Sharp & Dohme (MSD) and GlaxoSmithKline (GSK) have been confirmed to prevent high-risk HPV strains but these vaccines have been shown to be effective only in girls who have not been expos...
Small ubiquitin-like modifier (SUMO) fusion technology is widely used in the production of heterologous proteins from prokaryotic system to aid in protein solubilization and refolding. Due to an extensive clinical application of human bone morphogenetic protein 2 (hBMP2) in bone augmentation, total RNA was isolated from human gingival tissue and ma...
Background
The present study investigates the hepato- and DNA-protective effects of standardized extracts of Cleome brachycarpa (cabralealactone), Solanum incanum (solasodin), and Salvadora oleioides (salvadorin) in rats.
Materials and methods
Hepatotoxicity was induced with intraperitoneal injection of carbon tetrachloride (CCl4) (1 mL/kg b.wt.)...
Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progressi...
Disulphide bond (Dsb) protein, characterized as an important virulence factor in gram negative bacteria. In this study, amino acid mutations in DsbA signal sequence (ss) and its effect on translocation of recombinant Ovine growth hormone (rOGH) was observed. Eight constructs were designed on the basis of increased hydrophobicity and showed that hyd...
Breast cancer is characterized by an uncontrolled growth of cells in breast tissue. Genes that foster cell growth in breast cells are overexpressed, giving rise to breast tumors. The identification of effective inhibitors represents a rational chemopreventive strategy. The current in silico study provides a pharmacoinformatic approach for the ident...
Obesity is the worst health risk worldwide, which is linked to a number of diseases. Pancreatic lipase is considered as an affective cause of obesity and can be a major target for controlling the obesity. The present study was designed to find out best phytochemicals against pancreatic lipase through molecular docking combined with molecular dynami...
Scientific Reports 6 : Article number: 37313 10.1038/srep37313 ; published online: 09 December 2016 ; updated: 11 April 2017 In this Article, an affiliation was omitted for Muhammad Usman Mirza.
Purpose:To use in silico docking analysis and ADMET prediction of silibinin and glycyrrhetic acid to determine their pharmacokinetic and pharmacodynamic properties as therapeutic molecules against inflammatory disorders. Methods: The study utilized plant-derived compounds with known anti-inflammatory activity. Three important enzymes, including COX...
Hepatitis C virus (HCV) is one of the major viruses affecting the world today. It is a highly variable virus, having a rapid reproduction and evolution rate. The variability of genomes is due to hasty replication catalyzed by nonstructural protein 5B (NS5B) which is also a potential target site for the development of anti-HCV agents. Recently, the...
The present study was undertaken to explore the mechanism of paclitaxel induced apoptosis. Previous studies have shown that paclitaxel stabilizes microtubules and causes cell cycle arrest. It also acts through MAPK pathway. Moreover, the drug is known to inactivate antiapoptotic Bcl-2 family proteins. In this background we have undertaken this stud...
Parkinson’s disease (PD) is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currentl...
The rare hereditary disorder Fanconi Anemia (FA), a prototype example of DNA repair defect disorders with high cancer susceptibility, is an attractive model to study chromatin modifications and decipher their role in the context of DNA repair and cancer. There are many different enzymatic activities in the cell responsible for these chromatin modif...
Fanconi anemia (FA) is an autosomal and x-linked recessive genomic instability syndrome due to germ-line mutations in at least 15 DNA repair genes. FA has been associated with malignant cancers, most notably acute myeloid leukemia and squamous cell carcinomas of the head & neck (HNSCCs) origin. HNSCC is a malignant epithelial neoplasm that begins i...
Natural products including phytochemicals have been recently
proposed as tumor suppressors. In this paper, docking study is
presented to use these phytochemicals for their prospective role
in cancers including breast and prostate cancer. The most common type of cancer in women all over the world is breast cancer. The breast cells including cancerou...
Questions
Questions (4)
I have well resolved crystal structure and found one residue missing from the binding pocket of the protein. What are the key steps to perform it by using chimera or coot.
Need expert suggestions.
How I can find out the inhibitory effects of antiviral compounds by in silico methods? Is there any tool/server is available for the prediction of inhibitory effects of lead compounds?
We Need Collaboration: Our human molecular biology group recently performed CYP17 gene polymorphism association with Polycystic Ovarian Syndrome in number of patients (Paper write up has been completed up to that). We are interested to find out the Influence of Single Nucleotide Polymorphisms in Cytochrome P17 on Substrate Recognition Using Computational Docking and Molecular Dynamics Simulation. For this work I need some expert having command on Amber10/Gromacs. I'm interested to perform 20ns MD simulation and then see the effect of docking between CYP17 (Wild-type and mutants) and its inhibitor. If you are interested to perform this analysis. please contact me. (Authorship will be granted).
We are supposed to submit the paper in the month of February. Thanks
