Chemicals and Drugs Commons^™

Combined Use Of Donepezil And Memantine Increases The Probability Of Five-Year Survival Of Alzheimer’S Disease Patients, Ehsan Yaghmaei, Hongxia Lu, Louis Ehwerhemuepha, Jianwei Zheng, Sidy Danioko, Ahmad Rezaie, Seyed Ahmad Sajjadi, Cyril Rakovski

Mathematics, Physics, and Computer Science Faculty Articles and Research

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be beneficial in demonstrating which drugs reduce the disease burden and increase survival.

Methods

We conducted a comprehensive causal inference study implementing doubly robust estimators and using one of the largest high-quality medical databases, the Oracle Electronic Health Records (EHR) Real-World Data. Our work was focused on the estimation of the effects of the two common Alzheimer’s disease drugs, Donepezil and Memantine, and their combined use on the five-year survival since initial diagnosis of AD patients. …

Exploring Binding Pockets In The Conformational States Of The Sars-Cov-2 Spike Trimers For The Screening Of Allosteric Inhibitors Using Molecular Simulations And Ensemble-Based Ligand Docking, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike proteins are associated with the diversity of cryptic allosteric sites and complex molecular mechanisms that can be employed by allosteric ligands, including the alteration of the conformational equilibrium of spike protein and preferential stabilization of specific functional states. In the current study, we combine conformational dynamics analysis of distinct forms of the full-length spike protein trimers and …

Broad-Spectrum Activity Of Membranolytic Cationic Macrocyclic Peptides Against Multi-Drug Resistant Bacteria And Fungi, Sandeep Lohan, Anastasia G. Konshina, Rakesh K. Tiwari, Roman G. Efremov, Innokentiy Maslennikov, Keykavous Parang

Pharmacy Faculty Articles and Research

The emergence of multidrug-resistant (MDR) strains causes severe problems in the treatment of microbial infections owing to limited treatment options. Antimicrobial peptides (AMPs) are drawing considerable attention as promising antibiotic alternative candidates to combat MDR bacterial and fungal infections. Herein, we present a series of small amphiphilic membrane-active cyclic peptides composed, in part, of various nongenetically encoded hydrophilic and hydrophobic amino acids. Notably, lead cyclic peptides 3b and 4b showed broad-spectrum activity against drug-resistant Gram-positive (MIC = 1.5–6.2 µg/mL) and Gram-negative (MIC = 12.5–25 µg/mL) bacteria, and fungi (MIC = 3.1–12.5 µg/mL). Furthermore, lead peptides displayed substantial antibiofilm action comparable …

Ensemble-Based Mutational Profiling And Network Analysis Of The Sars-Cov-2 Spike Omicron Xbb Lineages For Interactions With The Ace2 Receptor And Antibodies: Cooperation Of Binding Hotspots In Mediating Epistatic Couplings Underlies Binding Mechanism And Immune Escape, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing of ACE2 binding and antibody evasion for Omicron variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.5 + L455F/F456L. By combining evolutionary analysis, molecular dynamics simulations, and ensemble-based mutational scanning of spike protein residues in complexes with ACE2, we identified structural stability and binding …

A Novel Micropeptide, Slitharin, Exerts Cardioprotective Effects In Myocardial Infarction, Ahmed G. E. Ibrahim, Alessandra Ciullo, Shukuro Yamaguchi, Chang Li, Travis Antes, Xaviar Jones, Liang Li, Ramachandran Murali, Innokentiy Maslennikov, Niveda Sundararaman, Daniel Soetkamp, Eugenio Cingolani, Jennifer Van Eyk, Eduardo Marbán

Pharmacy Faculty Articles and Research

Purpose: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type.

Experimental design: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction.

Results: We identified a novel 24-amino acid micropeptide …

Comparative Analysis Of Conformational Dynamics And Systematic Characterization Of Cryptic Pockets In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb.1 Spike Complexes With The Ace2 Host Receptor: Confluence Of Binding And Structural Plasticity In Mediating Networks Of Conserved Allosteric Sites, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes …

Exploring Conformational Landscapes And Cryptic Binding Pockets In Distinct Functional States Of The Sars-Cov-2 Omicron Ba.1 And Ba.2 Trimers: Mutation-Induced Modulation Of Protein Dynamics And Network-Guided Prediction Of Variant-Specific Allosteric Binding Sites, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

A significant body of experimental structures of SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and the emergence of druggable binding pockets. Understanding the interplay of conformational dynamics changes induced by the Omicron variants and the identification of cryptic dynamic binding pockets in the S protein is of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study, we explore conformational landscapes and characterize the universe of binding pockets in multiple open and closed functional spike states of the BA.1 and BA.2 Omicron …

Additive Effects Of Cyclic Peptide [R4w4] When Added Alongside Azithromycin And Rifampicin Against Mycobacterium Avium Infection, Melissa Kelley, Kayvan Sasaninia, Arbi Abnousian, Ali Badaoui, James Owens, Abrianna Beever, Nala Kachour, Rakesh Kumar Tiwari, Vishwanath Venketaraman

Pharmacy Faculty Articles and Research

Mycobacterium avium (M. avium), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional treatment consists of a 12-month regimen of the first-line antibiotics rifampicin and azithromycin. However, the treatment duration and low antibiotic tolerability present challenges in the treatment of M. avium infection. Furthermore, the emergence of multidrug-resistant mycobacterium strains prompts a need for novel treatments against M. avium infection. This study aims to test the efficacy of a novel antimicrobial peptide, cyclic [R4W4], alongside the first-line antibiotics azithromycin and rifampicin in reducing M. avium survival. Colony-forming unit (CFU) …

KCa2 And KCa3.1 Channels In The Airways: A New Therapeutic Target, Razan Orfali, Ali Alfaiz, Mohammad Asikur Rahman, Liz Lau, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

K⁺ channels are involved in many critical functions in lung physiology. Recently, the family of Ca²⁺-activated K⁺ channels (K_Ca) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of K_Ca channels, three small-conductance Ca²⁺-activated K⁺ (K_Ca2) channel subtypes, together with the intermediate-conductance K_Ca3.1 channel, are voltage-independent K⁺ channels, and they mediate Ca²⁺-induced membrane hyperpolarization. Many K_Ca2 channel members are involved in crucial roles in physiological and pathological …

Balancing Functional Tradeoffs Between Protein Stability And Ace2 Binding In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic And Energetic Changes, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and …

Coarse-Grained Molecular Simulations And Ensemble-Based Mutational Profiling Of Protein Stability In The Different Functional Forms Of The Sars-Cov-2 Spike Trimers: Balancing Stability And Adaptability In Ba.1, Ba.2 And Ba.2.75 Variants, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies have suggested that the emergence of Omicron variants can be determined by multiple fitness tradeoffs including immune escape, binding affinity, conformational plasticity, protein stability, and allosteric modulation. In this study, we embarked on a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the different functional states of spike trimers for BA.1, BA.2, and BA.2.75 variants. Using efficient and accurate coarse-grained simulations and atomistic reconstruction of the ensembles, we examined the conformational dynamics of the spike trimers that agree with the recent functional studies, suggesting that BA.2.75 trimers are the most stable …

Quantitative Phosphoproteomic Analysis Reveals Unique Camp Signaling Pools Emanating From Ac2 And Ac6 In Human Airway Smooth Muscle Cells, Isabella Cattani-Cavalieri, Yue Li, Jordyn Margolis, Amy S. Bogard, Moom R. Roosan, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Human airway smooth muscle (HASM) is the primary target of ßAR agonists used to control airway hypercontractility in asthma and chronic obstructive pulmonary disease (COPD). ßAR agonists induce the production of cAMP by adenylyl cyclases (ACs), activate PKA and cause bronchodilation. Several other G-protein coupled receptors (GPCR) expressed in human airway smooth muscle cells transduce extracellular signals through cAMP but these receptors elicit different cellular responses. Some G-protein coupled receptors couple to distinct adenylyl cyclases isoforms with different localization, partly explaining this compartmentation, but little is known about the downstream networks that result. We used quantitative phosphoproteomics to define the …

The Glycemic, Cholesterol, And Weight Effects Of L-Carnitine In Diabetes: A Systematic Review And Meta-Analysis Of Randomized Controlled Trials, Jennifer Ko, Eva Y. Wong, Huyentran N. Tran, Rebecca J.C. Tran, Diana X. Cao

Pharmacy Faculty Articles and Research

Introduction

L-carnitine possibly impacts insulin sensitivity and glucose metabolism. However, its therapeutic role in diabetes is poorly understood.

Methods

A systematic review and meta-analysis were conducted using PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception through June 30, 2021. Included studies evaluated the use of L-carnitine in diabetes on fasting blood glucose (FBG), hemoglobin A1c (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), weight, or body mass index (BMI). Weighted mean difference (WMD) and 95% confidence intervals (CI) were calculated using the DerSimonian and Laird random-effects model.

Results

Seventeen studies …

Protein Phosphatase 2a Regulates Xanthine Oxidase-Derived Ros Production In Macrophages And Influx Of Inflammatory Monocytes In A Murine Gout Model, Sandy Elsayed, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Background: Gout is a common arthritis, due to deposition of monosodium urate (MSU) crystals which results in IL-1β secretion by tissue-resident macrophages. Xanthine oxidase (XO) catalyzes uric acid (UA) production and in the process, reactive oxygen species (ROS) are generated which contributes to NLRP3 inflammasome activation. Protein phosphatase 2A (PP2A) may be involved in regulating inflammatory pathways in macrophages. The objective of this study was to investigate whether PP2A regulates gout inflammation, mediated by XO activity modulation. We studied UA and ROS generations in MSU stimulated murine bone marrow derived macrophages (BMDMs) in response to fingolimod phosphate, a PP2A activator, …

Effects Of Chronic Cirrhosis Induced By Intraperitoneal Thioacetamide Injection On The Protein Content And Michaelis–Menten Kinetics Of Cytochrome P450 Enzymes In The Rat Liver Microsomes, Devaraj Venkatapura Chandrashekar, Barent N. Dubois, Mamunur Rashid, Reza Mehvar

Pharmacy Faculty Articles and Research

Chronic intraperitoneal injection of thioacetamide (TAA) in rats has been used as an animal model of human cirrhosis to study the effects of the disease on drug metabolism. However, TAA inhibits P450 enzymes directly and independently of cirrhosis. We investigated the effects of chronic cirrhosis in rats, induced by 10 weeks of intraperitoneal TAA, on the P450 enzymes after a 10-day washout period to eliminate TAA. Liver histology and serum biomarkers of hepatic function confirmed cirrhosis in all animals. Microsomal total P450 content, P450 reductase activity and ethoxycoumarin O-deethylase activity, a general marker of P450 activity, were significantly reduced by …

Targeted Next-Generation Sequencing Of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants In Patients With Iodide Transport Defect, Carlos Eduardo Bernal Barquero, Romina Celeste Geysels, Virginie Jacques, Gerardo Hérnan Carro, Mariano Martín, Victoria Peyret, María Celeste Abregú, Patricia Papendieck, Ana María Masini-Repiso, Frédérique Savagner, Ana Elena Chiesa, Cintia E. Citterio, Juan Pablo Nicola

Pharmacy Faculty Articles and Research

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Synthesis And Evaluation Of Anti-Hiv Activity Of Mono- And Di-Substituted Phosphonamidate Conjugates Of Tenofovir, Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui, Keykavous Parang

Pharmacy Faculty Articles and Research

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several …

Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

n this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the …

Full- Versus Sub-Regional Quantification Of Amyloid-Beta Load On Mouse Brain Sections, Yuu Ohno, Riley Murphy, Matthew Choi, Weijun Ou, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Extracellular accumulation of amyloid-beta (Aβ) plaques is one of the major pathological hallmarks of Alzheimer's disease (AD), and is the target of the only FDA-approved disease-modifying treatment for AD. Accordingly, the use of transgenic mouse models that overexpress the amyloid precursor protein and thereby accumulate cerebral Aβ plaques are widely used to model human AD in mice. Therefore, immunoassays, including enzyme-linked immunosorbent assay (ELISA) and immunostaining, commonly measure the Aβ load in brain tissues derived from AD transgenic mice. Though the methods for Aβ detection and quantification have been well established and documented, the impact of the size of the …

A Small Peptide Increases Drug Delivery In Human Melanoma Cells, Shirley Tong, Shaban Darwish, Hanieh Hossein Nejad Ariani, Kate Alison Lozada, David Salehi, Maris A. Cinelli, Richard B. Silverman, Kamaljit Kaur, Sun Yang

Pharmacy Faculty Articles and Research

Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa …

Biophysical Insight Into The Sars-Cov2 Spike–Ace2 Interaction And Its Modulation By Hepcidin Through A Multifaceted Computational Approach, Hamid Hadi-Alijanvand, Luisa Di Paola, Guang Hu, David M. Leitner, Gennady M. Verkhivker, Peixin Sun, Humanath Poudel, Alessandro Giuliani

Mathematics, Physics, and Computer Science Faculty Articles and Research

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection …

Targeting Neuronal Nitric Oxide Synthase (Nnos) For Melanoma Treatment, Shirley Tong

Pharmaceutical Sciences (PhD) Dissertations

Human cutaneous melanoma is the most aggressive form of skin cancer and the incidence rates have continued to increase over the years. Neuronal nitric oxide synthase (nNOS) produces nitric oxide (NO) has been found to be overexpressed in human melanoma and the expression of nNOS is induced by interferon-gamma (IFN-γ). In our studies, nNOS has been implicated in IFN-γ-stimulated melanoma progression and the inhibition of nNOS using novel inhibitors effectively inhibited IFN-γ-stimulated tumor growth in a xenograft mouse model. Programmed death-ligand 1 (PD-L1) is overexpressed in melanoma and plays an important role in suppressing the immune system ^12-14. Our …

Interactions Among Endothelial Nitric Oxide Synthase, Cardiovascular System, And Nociception During Physiological And Pathophysiological States, Niribili Sarmah, Andromeda M. Nauli, Ahmmed Ally, Surya M. Nauli

Pharmacy Faculty Articles and Research

Nitric oxide synthase (NOS) plays important roles within the cardiovascular system in physiological states as well as in pathophysiologic and specific cardiovascular (CV) disease states, such as hypertension (HTN), arteriosclerosis, and cerebrovascular accidents. This review discusses the roles of the endothelial NOS (eNOS) and its effect on cardiovascular responses that are induced by nociceptive stimuli. The roles of eNOS enzyme in modulating CV functions while experiencing pain will be discussed. Nociception, otherwise known as the subjective experience of pain through sensory receptors, termed “nociceptors”, can be stimulated by various external or internal stimuli. In turn, events of various cascade pathways …

Author Correction: Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas

Pharmacy Faculty Articles and Research

Correction to: Scientific Reports https://doi.org/10.1038/s41598-019-47255-9, published online 29 July 2019

The original Article contained an error in Figure 1A where the control trace for both the HEK-AMY3 and HEKWT cells was duplicated...

The original Article has been corrected.

Computer Simulations And Network-Based Profiling Of Binding And Allosteric Interactions Of Sars-Cov-2 Spike Variant Complexes And The Host Receptor: Dissecting The Mechanistic Effects Of The Delta And Omicron Mutations, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we combine all-atom MD simulations and comprehensive mutational scanning of S-RBD complexes with the angiotensin-converting enzyme 2 (ACE2) host receptor in the native form as well as the S-RBD Delta and Omicron variants to (a) examine the differences in the dynamic signatures of the S-RBD complexes and (b) identify the critical binding hotspots and sensitivity of the mutational positions. We also examined the differences in allosteric interactions and communications in the S-RBD complexes for the Delta and Omicron variants. Through the perturbation-based scanning of the allosteric propensities of the SARS-CoV-2 S-RBD residues and dynamics-based network centrality and …

Quadruped Gait And Regulation Of Apoptotic Factors In Tibiofemoral Joints Following Intra-Articular Rhprg4 Injection In Prg4 Null Mice, Daniel S. Yang, Edward E. Dickerson, Ling X. Zhang, Holly Richendrfer, Padmini N. Karamchedu, Gary A. Badger, Tannin A. Schmidt, Alger M. Fredericks, Khaled A. Elsaid, Gregory D. Jay

Pharmacy Faculty Articles and Research

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome leads to diarthrodial joint arthropathy and is caused by the absence of lubricin (proteoglycan 4—PRG4), a surface-active mucinous glycoprotein responsible for lubricating articular cartilage. In this study, mice lacking the orthologous gene Prg4 served as a model that recapitulates the destructive arthrosis that involves biofouling of cartilage by serum proteins in lieu of Prg4. This study hypothesized that Prg4-deficient mice would demonstrate a quadruped gait change and decreased markers of mitochondrial dyscrasia, following intra-articular injection of both hindlimbs with recombinant human PRG4 (rhPRG4). Prg4^−/− (N = 44) mice of both sexes were injected with rhPRG4 …

Dissecting Mutational Allosteric Effects In Alkaline Phosphatases Associated With Different Hypophosphatasia Phenotypes: An Integrative Computational Investigation, Fei Xiao, Ziyun Zhou, Xingyu Song, Mi Gan, Jie Long, Gennady M. Verkhivker, Guang Hu

Mathematics, Physics, and Computer Science Faculty Articles and Research

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of ALPL mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the ALPL mutations on protein dynamics and function. Statistical analysis of molecular features computed for the …

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …

Cilia Proteins Are Biomarkers Of Altered Flow In The Vasculature, Ankan Gupta, Karthikeyan Thirugnanam, Madhan Thamilarasan, Ashraf M. Mohieldin, Hadeel T. Zedan, Shubhangi Prabhudesai, Meghan R. Griffin, Andrew D. Spearman, Amy Pan, Sean P. Palecek, Huseyin C. Yalcin, Surya M. Nauli, Kevin R. Rarick, Rahima Zennadi, Ramani Ramchandran

Pharmacy Faculty Articles and Research

Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as low-flow sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation—the physical removal of cilia from the cell surface—is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress would manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress …