About Hussain Basha Syed
Head, Research and Development (Oct, 2013 - Current)Innovative Informatica Technologies
Currently working as Head, R&D activities at Innovative Informatica Technologies in the research area of Chemoinformatics and computational biology for novel drug discovery. Designing and execution of innovative research projects, thus helping clients for their successful completion of the projects involves my primary responsibility along with administration of technical business activities.
B.Sc Biochemistry (Jun, 2006 - Apr, 2009)Acharya Nagarjuna University
Bachelors in Biochemistry with Chemistry and Botany.
M.Sc Biotechnology (Sep, 2009 - Jul, 2011)Bangalore University
Masters in Biotechnology
Honours & Awards
A Comprehensive In Silico Analysis on the Structural and Functional Impact of SNPs in the Congenital Heart Defects Associated with NKX2-5 Gene—A Molecular Dynamic Simulation Approach (May 05, 2016)
Congenital heart defects (CHD) presented as structural defects in the heart and blood vessels during birth contribute an important cause of childhood morbidity and mortality worldwide. Many Single nucletotide polymorphisms (SNPs) in different genes have been associated with various types of congenital heart defects. NKX 2–5 gene is one among them, which encodes a homeobox-containing transcription factor that plays a crucial role during the initial phases of heart formation and development. Mutations in this gene could cause different types of congenital heart defects, including Atrial septal defect (ASD), Atrial ventricular block (AVB), Tetralogy of fallot and ventricular septal defect. This highlights the importance of studying the impact of different SNPs found within this gene that might cause structural and functional modification of its encoded protein. In this study, we retrieved SNPs from the database (dbSNP), followed by identification of potentially deleterious Non-synonymous single nucleotide polymorphisms (nsSNPs) and prediction of their effect on proteins by computational screening using SIFT and Polyphen. Furthermore, we have carried out molecular dynamic simulation (MDS) in order to uncover the SNPs that would cause the most structural damage to the protein altering its biological function. The most important SNP that was found using our approach was rs137852685 R161P, which was predicted to cause the most damage to the structural features of the protein. Mapping nsSNPs in genes such as NKX 2–5 would provide valuable information about individuals carrying these polymorphisms, where such variations could be used as diagnostic markers.
Pharmacophore feature-based virtual screening for finding potent GSK-3 inhibitors using molecular docking and dynamics simulations: (November 11, 2016)
Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer\\\\\\\\'s disease. In the present study, we performed pharmacophore feature-based virtual screening for identifying potent targetspecific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.
Insights from the predicted structural analysis of carborane substituted withaferin A with Indoleamine - 2,3-dioxygenase as a potent inhibitor (November 11, 2016)
Indoleamine-2,3-dioxygenase (IDO) an immunoregulatory enzyme and emerging as a new therapeutic drug target for the treatment of cancer. Carboranes, an icosahedral arrangement of eleven boron atoms plus one carbon atom with unique pharmacological properties such low toxicity, isosterism with phenyl ring and stability to hydrolysis. On the other hand, carboranes are known to increase the interaction of ligand with non-polar region of the protein provides an excellent platform to explore these carboranes towards designing and development of novel, potent and target specific drug candidates with further enhanced binding affinities. Despite of their many potential applications, molecular modeling studies of carborane-substituted ligands with macromolecules have been rarely reported. Previously, we have demonstrated the promising high binding affinity of Withaferin-A (WA) for IDO. In this present study, we investigated the effect of carborane substitutions on WA compound towards developing novel analogs for target specific IDO inhibition with better potency. Interesting docked poses and molecular interactions for the carborane substituted WA ligands were elucidated. Based on our In-silico studies, carborane substituted at various position of WA has shown enhanced binding affinity towards IDO, worth of considering for further studies.
Molecular docking based screening of novel designed chalcone series of compounds for their anti-cancer activity targeting EGFR kinase domain (July 07, 2015)
Epidermal growth factor receptors (EGFR) are critical for the growth of many tumors and expressed at high levels in about one third of epithelial cancers. Hence, blockade of the binding sites for EGFR has been hypothesized as an effective anti-cancer therapy. Chalcone derivative compounds have been shown to be highly effective anti-cancer agents, however there are still so many novel derivatives possible, one of which might get us the best targeted EGFR inhibitor. In this effort directed towards the discovery of novel, potent anti-tumor agents for the treatment of cancer, in the present study a library of novel chalcone series of compounds has been designed and evaluated for their anti-cancer activity targeting EGFR kinase domain using various computational approaches. Among the twenty five novel designed chalcone series of compounds, all of them have found to be successfully docking inside the active binding domain of EGFR receptor target with a binding energy in a range of -6.10 to -9.25 Kcal/mol with predicted IC50 value range of 33.50 micor molar to 164.66 nano molar respectively. On the other hand, calculated 2DQSAR molecular descriptor properties of the compounds showed promising ADME parameters and found to be well in compliance with Lipinski’s rule of five. Among all the twenty five compounds tested, compound 21 ((2E)-3-(anthracen-9-yl)-1-phenylprop-2-2n-1-one) was found to be the best lead like molecule with a binding energy of -9.25 kcal/mol with predicted IC50 value of 164.66 nano molar. Conclusively, novel designed compound 21 of the present study have shown promising anti-cancer potential worth considering for further evaluations.
Noninvasive cellular internalization of silver molecules by chitosan nanoneedles: a novel nanocarrier (June 06, 2015)
We explore with molecular modeling, dynamics simulations, and a statistical model the ability of chitosan nanoneedles (CNNs) to be internalized into a model lipid bilayer as a function of their length, keeping in view of their applications in the field of biomedicine for advanced targeted drug delivery. In this study, we have computationally modeled and studied the structural geometry and the stability of CNNs formed by 4, 6, and 8 subunits. We reported the molecular surface analysis of the modeled CNNs along with molecular dynamic (MD) simulations studies toward revealing the noninvasive cellular internalization potential of these CNNs and a case study has been carried to study the ability of CNNs to translocate silver nanoparticles across membrane. The present results are strongly in support of further exploration of 8 subunits based CNNs for their application as target drug delivery vehicles. The hydrophilicity of the CNNs has been attributed as one of the key factors responsible for the internalization process. Moreover, our MD simulation studies marched the ability of CNNs to translocate silver nanoparticles through biological membrane in a similar manner that resembles cell-penetrating peptides.
Molecular docking and dynamic simulation studies evidenced plausible immunotherapeutic anticancer property by Withaferin A targeting indoleamine 2, 3-dioxygenase (February 02, 2015)
Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic drug target for the treatment of cancer characterized by pathological immune suppression. IDO catalyzes the rate-limiting step of tryptophan degradation along the kynurenine pathway. Reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to the immunosuppressive effects of IDO. Presence of IDO on dentritic cells in tumor-draining lymph nodes leading to the activation of T cells toward forming immunosuppressive microenvironment for the survival of tumor cells has confirmed the importance of IDO as a promising novel anticancer immunotherapy drug target. On the other hand, Withaferin A (WA) – active constituent of Withania Somnifera ayurvedic herb has shown to be having a wide range of targeted anticancer properties. In the present study conducted here is an attempt to explore the potential of WA in attenuating IDO for immunotherapeutic tumor arresting activity and to elucidate the underlying mode of action in a computational approach. Our docking and molecular dynamic simulation results predict high binding affinity of the ligand to the receptor with up to −11.51 kcal/mol of energy and 3.63 nM of IC50 value. Further, de novo molecular dynamic simulations predicted stable ligand interactions with critically important residues SER167; ARG231; LYS377, and heme moiety involved in IDO’s activity. Conclusively, our results strongly suggest WA as a valuable small ligand molecule with strong binding affinity toward IDO.
Anti-angiogenesis property by Quercetin compound targeting VEGFR2 elucidated in a computational approach (December 12, 2014)
Quercetin is a naturally occurring flavonoid compound found in various species of vegetables and fruits. This compound have been widely demonstrated for having various medicinal properties including its capacity to inhibit enzymes that activate carcinogens, anti-viral, antioxidative activity as well as to modify signal transduction pathways by interacting with regulatory cell receptors etc., On the other hand, recent reports have evidenced significant anti-angiogenesis property of this compound on rat models targeting VEGFR2 regulated signalling pathways. In this scenario, we have carried out this present study to elucidate the underlying interactions responsible for this strong target specific inhibition at the molecular level using different computational approaches. Our docking, binding free energy along with molecular dynamic simulation studies revealed various interactions responsible for this target specific binding involving large negative binding energies. Quercetin compound demonstrated out ruling properties and interactions when compared the results with the VEGFR2 co-crystallized ligand AAZ. The present results would be of high value for further designing potent target specific anti-angiogenesis drug compounds.
Computational repositioning of ethno medicine elucidated gB-gH-gL complex as novel anti herpes drug target (April 04, 2013)
Herpes viruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity. They remain latent in the host cells and can cause recurrent infections that might prove fatal. These viruses are known to infect the host cells by causing the fusion of viral and host cell membrane proteins. Fusion is achieved with the help of conserved fusion machinery components, glycoproteins gB, heterodimer gH-gL complex along with other non-conserved components. Whereas, another important glycoprotein gD without which viral entry to the cell is not possible, acts as a co-activator for the gB-gH-gL complex formation. Thus, this complex formation interface is the most promising drug target for the development of novel anti-herpes drug candidates. In the present study, we propose a model for binding of gH-gL to gB glycoprotein leading from pre to post conformational changes during gB-gH-gL complex formation and reported the key residues involved in this binding activity along with possible binding site locations. To validate the drug targetability of our proposed binding site, we have repositioned some of the most promising in vitro, in vivo validated anti-herpes molecules onto the proposed binding site of gH-gL complex in a computational approach. Successful repositioning of the analyzed compounds onto the proposed binding site confirms the drug targetability of gH-gL complex. Based on the free binding energy and pharmacological properties, we propose (3-chloro phenyl) methyl-3,4,5 trihydroxybenzoate as worth a small ethno medicinal lead molecule for further development as potent anti-herpes drug candidate targeting gB-gH-gL complex formation interface.
Ligand and Structure Based Virtual Screening Studies to Identify Potent Inhibitors against Herpes Virus Targeting gB-gH-gL Complex Interface as a Novel Drug Target (January 01, 2012)
Glycoproteins gB and gH-gL are highly conserved cell entry machinery, which are involved in attachment and fusion of herpes virus to the host cell. gB is a homotrimer with structural characteristics to undergo conformational rearrangement when triggered, thus inferred to be the effector of viral fusion, whereas, gH-gL glycoprotein is a heterodimer complex proposed to be the activator of gB glycoprotein, probably through direct binding. Critical dependence of herpes virus on the formation of this gB-gH-gL complex for its entry into the host cell, making this interface a promising anti herpes drug target. Arresting this complex formation by blocking the interactions between the key residues of these glycoproteins seems to be the most promising mechanism to inhibit the viral infection. From our previous research, we identified (3-Chloro Phenyl) Methyl-3,4,5 Trihydroxybenzoate (CPMTHB) as a potent inhibitor for gH-gL heterodimer complex. In this present study, a ligand based virtual screening with a threshold of >50% similarity was performed, based on the structure of CPMTHB using ZINC database, and resulted 505 compounds were utilized to perform a structure based virtual screening on glycoproteins gB and gH-gL complex separately, targeting key residues involved in their binding activity. 31 compounds were identified as better inhibitors based on free binding energy and ADMET constraints, compared to CPMTHB. The capability of CPMTHB and 31 better compounds to disrupt gB-gH-gL complex formation was evident from our flexible and semi-flexible docking studies, suggesting the possible mode of action of these tested compounds to inhibit herpes virus, is by attenuating this complex formation, thus leaving significant evidence in support of this complex as a promising anti herpes drug target.
gB-gH-gL complex, a novel anti herpes drug target elucidated in molecular docking studies (ABSTRACT) (July 07, 2017)
gB–gH–gL complex formation possibly through direct binding is critical for Herpes infection, thus making the gB–gH–gL interface a promising antiviral target. In this present study, we identified the key residues involved in this complex formation and identified some of the most promising compounds which showed significant capability to attenuate this complex formation through structure based coupled with ligand based virtual screening along with semi-flexible and flexible docking studies with ADMET constraints.
In-Silico screening of Pleconaril and its novel substituted derivatives with Neuraminidase of H1N1 Influenza strain (February 02, 2012)
Background: Neuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication. Anti influenza drugs such as Oseltamivir target a highly conserved active site of NA, which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) to restrict viral release from host cells, thus inhibiting its ability to cleave sialic acid residues on the cell membrane. Reports on the emergence of Oseltamivir resistant strains of H1N1 Influenza virus necessitated a search for alternative drug candidates. Pleconaril is a novel antiviral drug being developed by Schering-Plough to treat Picornaviridae infections, and is in its late clinical trials stage. Since, Pleconaril was designed to bind the highly conserved hydrophobic binding site on VP1 protein of Picorna viruses, the ability of Pleconaril and its novel substituted derivatives to bind highly conserved hydrophobic active site of H1N1 Neuraminidase, targeting which oseltamivir has been designed was investigated. Results: 310 novel substituted variants of Pleconaril were designed using Chemsketch software and docked into the highly conserved active site of NA using arguslab software. 198 out of 310 Pleconaril variants analyzed for docking with NA active site were proven effective, based on their free binding energy. Conclusion: Pleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.
Pleconaril as a Neuraminidase Inhibitor for H1N1 Influenza strain – comparative docking analysis with Oseltamivir (December 12, 2010)
Abstract: Neuraminidase (NA) enzyme of Influenza-A virus cleaves sialic acid residues from viral and mammalian cell wall glycoconjugates and helps in the release of virions post replication. Sialic acid cleaving activity makes NA most obvious choice for targeted drug designing against influenza. There has been as upsurge of interest in finding effective alternatives to the existing anti-influenza drugs in the wake of emergence of oseltamivir resistant viral strains. The present work demonstrated pleconaril as an effective alternative to oseltamivir against influenza based on active site analysis, molecular docking and binding energy studies on NA.