Alexander MacKerell

Alexander MacKerell
University of Maryland, Baltimore | UMB · Department of Pharmaceutical Sciences (PSC)

About

636
Publications
63,077
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83,988
Citations
Citations since 2017
161 Research Items
43241 Citations
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201720182019202020212022202302,0004,0006,0008,000
Introduction
Skills and Expertise

Publications

Publications (636)
Chapter
Computer-aided drug design (CADD) approaches are playing an increasingly important role in understanding the fundamentals of ligand-receptor interactions and helping medicinal chemists design therapeutics. About 5 years ago, we presented a chapter devoted to an overview of CADD methods and covered typical CADD protocols including structure-based dr...
Article
Activation of β 2 -adrenoceptors (β 2 ARs) causes airway smooth muscle (ASM) relaxation and bronchodilation, and β 2 AR agonists (β-agonists) are front-line treatments for asthma and other obstructive lung diseases. However, the therapeutic efficacy of β-agonists is limited by agonist-induced β 2 AR desensitization and noncanonical β 2 AR signaling...
Article
Molecular dynamic simulations are an effective tool to study complex molecular systems and are contingent upon the availability of an accurate and reliable molecular mechanics force field. The Drude polarizable force field, which allows for the explicit treatment of electronic polarization in a computationally efficient fashion, has been shown to r...
Article
Generalized force fields (FFs) act as extensions to biomolecular FFs to provide a wide coverage of organic molecules. However, their precise application to an arbitrary molecule presents a separate challenge. We show that MATCH assigns different atom types and bonded and nonbonded parameters than CGenFF, and the AM1-BCC charge model, commonly used...
Article
RNA molecules can act as potential drug targets in different diseases, as their dysregulated expression or misfolding can alter various cellular processes. Noncoding RNAs account for ∼70% of the human genome, and these molecules can have complex tertiary structures that present a great opportunity for targeting by small molecules. In the present st...
Article
FcγRIIIa-FcεRIγ complexes, upon stimulation by antibodies, cluster to initiate intracellular signaling and activate natural killer (NK) cells. Intracellular signaling involves Lck phosphorylation of ITAMs of each monomer of a FcεRIγ homodimer in a FcγRIIIa-FcεRIγ complex and subsequent binding of two phosphotyrosines (pY) in tandem by a Syk family...
Article
Full-text available
The human ether-a-go-go-related gene (hERG) potassium channel is a well-known contributor to drug-induced cardiotoxicity and therefore is an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to p...
Article
Overexpression of the anti-apoptotic BCL-2 proteins is associated with the development and progression of a range of cancers. Venetoclax, an FDA-approved BCL-2 inhibitor, is fast becoming the standard-of-care for acute myeloid leukemia and chronic lymphocytic leukemia. However, the median survival offered by venetoclax is only 18 months (as part of...
Preprint
Human ether-a-go-go-related gene (hERG) potassium channel is well-known contributor to drug-induced cardiotoxicity and therefore an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to predict hE...
Poster
Objective & hypothesis: Activation of β2 -adrenergic receptors (β2 ARs) leads to airway smooth muscle (ASM) relaxation and bronchodilation. While this facilitates β2 ARs agonists (β-agonists) as the front-line treatments for asthma and related obstructive airway diseases, their therapeutic efficacy of β-agonists is limited by agonist-induced β2 AR...
Article
Full-text available
The focus of the current study is to investigate cholecalciferol (vitamin D3) solubilization by hydroxypropyl-β-cyclodextrin (HPBCD) complexation through experimental and computational studies. Phase solubility diagram of vitamin D3 (completely insoluble in water) has an AP profile revealing a deviation from a linear regression with HPBCD concentra...
Article
Full-text available
D-Mannose is a structural component in N-linked glycoproteins from viruses and mammals as well as in polysaccharides from fungi and bacteria. Structural components often consist of D-Manp residues joined via...
Article
Explicit treatment of electronic polarizability in empirical force fields (FFs) represents an extension over a traditional additive or pairwise FF and provides a more realistic model of the variations in electronic structure in condensed phase, macromolecular simulations. To facilitate utilization of the polarizable FF based on the classical Drude...
Article
Molecular dynamics (MD) simulations play a crucial role in modeling biomolecular systems in which the electrostatic interactions are critical in dictating the structural and dynamical properties. Thus, the treatment of the electrostatic interactions defined in the underlying force field (FF) strongly affects the simulation accuracy. Most FFs use fi...
Article
Potential energy parameters for α-methyl amino acids were generated with ab initio calculations on α-methyl-N-acetylalanyl-N′-methylamide (the α-methyl “alanine dipeptide”) which served as an input to a grid-based correction to the backbone torsional potential (known as CMAP) consistent with the CHARMM36m additive protein force field. The new param...
Article
Full-text available
The innate immune system is the body's first line of defense against pathogens and its protection against infectious diseases. On the surface of host myeloid cells, Toll-like receptor 4 (TLR4) senses lipopolysaccharide (LPS), the major outer membrane component of Gram-negative bacteria. Intracellularly, LPS is recognized by caspase 11 through the n...
Article
Full-text available
Antibodies bind foreign antigens with high affinity and specificity leading to their neutralization and/or clearance by the immune system. The conserved N-glycan on IgG has significant impact on antibody effector function, with the endoglycosidases of Streptococcus pyogen es deglycosylating the IgG to evade the immune system, a process catalyzed by...
Article
Full-text available
Predicting relative protein-ligand binding affinities is a central pillar of lead optimization efforts in structure-based drug design. The Site Identification by Ligand Competitive Saturation (SILCS) methodology is based on functional...
Preprint
Full-text available
Antibodies bind foreign antigens with high affinity and specificity leading to their neutralization and/or clearance by the immune system. The conserved N-glycan on IgG has significant impact on antibody effector function, with the endoglycosidases of Streptococcus pyogen es deglycosylating the IgG to evade the immune system, a process catalyzed by...
Article
Small molecules such as metabolites and drugs must pass through the membrane of the cell, a barrier primarily comprising phospholipid bilayers and embedded proteins. To better understand the process of passive diffusion, knowledge of the ability of various functional groups to partition across bilayers and the associated energetics would be of util...
Article
B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcription...
Article
Second-generation ethanol production involves the use of agricultural and forestry waste as feedstock, being an alternative to the first-generation technology as it relies on low-cost abundant residues and does not affect food agriculture. However, the success of second-generation biorefineries relies on energetically efficient processes and effect...
Article
Full-text available
Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thor...
Article
The development of the CHARMM lipid force field (FF) can be traced back to the early 1990s with its current version denoted CHARMM36 (C36). The parametrization of C36 utilized high-level quantum mechanical data and free energy calculations of model compounds before parameters were manually adjusted to yield agreement with experimental properties of...
Article
Despite the progress in modeling complex molecular systems of ever-increasing complexity, a quantitatively accurate computational treatment of ion permeation through narrow membrane channels remains challenging. An important factor to reach this goal is induced electronic polarization, which is likely to impact the permeation rate of small ions thr...
Article
Full-text available
β-lactam antibiotics are the most widely used antimicrobial agents since the discovery of benzylpenicillin in the 1920s. Unfortunately, these life-saving antibiotics are vulnerable to inactivation by continuously evolving β-lactamase enzymes that are primary resistance determinants in multi-drug resistant pathogens. The current study exploits the s...
Article
Rapidly synthesis of suitable drug candidates using both a simple cyclophane synthesis and the fragmap method of SILCS in computational chemistry is reported in this work. The cover image depicts cyclophane synthesis using a waffle‐making device so that it is easy to imagine that cyclophane derivatives can be quickly synthesized by heat. More infor...
Article
Full-text available
S100B, a biomarker of malignant melanoma, interacts with the p53 protein and diminishes its tumor suppressor function, which makes this S100 family member a promising therapeutic target for treating malignant melanoma. However, it is a challenge to design inhibitors that are specific for S100B in melanoma versus other S100-family members that are i...
Article
Full-text available
We have identified chemical probes that simultaneously inhibit cancer cell progression and an immune checkpoint. Using the computational Site Identification by Ligand Competitive Saturation (SILCS) technology, structural biology and cell-based assays, we identify small molecules that directly and selectively bind to the RNA Recognition Motif (RRM)...
Article
Site Identification by Ligand Competitive Saturation (SILCS) is a molecular simulation approach that uses diverse small solutes in aqueous solution to obtain functional group affinity patterns of a protein or...
Preprint
The development of the CHARMM lipid force field (FF) can be traced back to the early 1990s with its current version denoted CHARMM36 (C36). The parametrization of C36 utilized high-level quantum mechanical data and free energy calculations of model compounds before parameters were manually adjusted to yield agreement with experimental properties of...
Article
CITCO (6-(4-chlorophenyl)im­i­dazo[2,1-b][1,3]thi­a­zole-5-car­balde­hyde-O-(3,4-dichloroben­zyl) oxime) is a widely used ag­o­nist of the hu­man con­sti­tu­tive an­drostane re­cep­tor (hCAR), a key he­patic xeno­bi­otic sen­sor pro­tein with emerg­ing ther­a­peu­tic in­di­ca­tions. To ad­dress the in­suf­fi­cient sta­bil­ity of CITCO, which lim­it...
Article
Significance The SARS-CoV-2 pandemic of 2020 has highlighted the great need for antiviral therapeutics. In this work, we identify a host factor, the SKI complex, is involved in replication of influenza and coronaviruses. Using computational modeling we were able to identify chemicals that interact with the host factor that display broad-spectrum an...
Article
Drug-induced cardiotoxicity is a potentially lethal and yet one of the most common side effects with the drugs in clinical use. Most of the drug-induced cardiotoxicity is associated with an off-target pharmacological blockade of K+ currents carried out by the cardiac Human-Ether-a-go-go-Related (hERG1) potassium channel. There is a compulsory precl...
Article
Formulation of protein-based therapeutics employ advanced formulation and analytical technologies for screening various parameters such as buffer, pH, and excipients. At a molecular level, physico-chemical properties of a protein formulation depend on self-interaction between protein molecules, protein-solvent and protein-excipient interactions. Th...
Article
Protein therapeutics typically require a concentrated protein formulation, which can lead to self-association and/or high viscosity due to protein-protein interaction (PPI). Excipients are often added to improve stability, bioavailability, and manufacturability of the protein therapeutics, but the selection of excipients often relies on trial and e...
Article
Polarizable force fields based on classical Drude oscillators offer a practical and computationally efficient avenue to carry out molecular dynamics (MD) simulations of large biomolecular systems. To treat the polarizable electronic degrees of freedom, the Drude model introduces a virtual charged particle that is attached to its parent nucleus via...
Article
A simple approach to the synthesis of heterocyclophane consisting of two 4,4’‐bithiazoles has been developed in mild conditions. The heterocyclophane with two short chains was conveniently prepared by Hantzsch thiazoles synthesis using the reaction of 3‐ tert ‐butoxycarbonyl‐3‐azapentanethiocarboxamide with 1,4‐dibromobutane‐2,3‐dione in methanol u...
Article
Native folded and compact intermediate states of RNA typically involve tertiary structures in the presence of divalent ions such as Mg2+ in a background of monovalent ions. In a recent study we have shown how the presence of Mg2+ impacts the transition from partially unfolded to folded states through a "push-pull" mechanism where the ion both favor...
Chapter
Computational methods are useful tools to assist and interact with experiment techniques to expedite the drug design process in general. Provided here is an introduction of well-established and newly developed computer-aided drug design (CADD) approaches that are regularly being used in the development of kinase inhibitors. This includes methods fr...
Article
Starting from a yeast suppressor screening platform, we have identified the SKI complex as a potential broad-spectrum antiviral target. We found that the NS1 protein of influenza A virus (IAV) and the ORF4a protein of Middle East respiratory syndrome coronavirus (MERS-CoV), which both function to bind double-strand RNA and inhibit cellular interfer...
Preprint
Full-text available
Native folded and compact intermediate states of RNA typically involve tertiary structures in the presence of divalent ions such as Mg2+ in a background of monovalent ions. In a recent study we showed how the presence of Mg2+ impacts the transition from partially unfolded to folded states through a "push-pull" mechanism where the ion both favors an...
Article
Protein–protein interactions (PPIs), many of which are dominated by α‐helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl‐2 protein family can lead to several diseases including cancer, neurodegenera...
Article
Electronic polarization effects have been suggested to play an important role in proton binding to titratable residues in proteins. In this work, we describe a new computational method for pKa calculations, using Monte Carlo (MC) simulations to sample protein protonation states with the Drude polarizable force field and Poisson-Boltzmann (PB) conti...
Article
Polarizable force fields are emerging as a more accurate alternative to additive force fields in terms of modeling and simulations of a variety of chemicals including biomolecules. Explicit treatment of induced polarization in charged species such as phosphates and sulfates offers the potential for achieving an improved atomistic understanding of t...
Article
The CHARMM Drude-2013 polarizable force field (FF) was developed to include the explicit treatment of induced electronic polarizability, resulting in a more accurate description of the electrostatic interactions in molecular dynamics (MD) simulations. While the Drude-2013 protein FF has shown success in improving the folding properties of α-helical...
Article
Interactions of proteins with functional groups are key to their biological functions, making it essential that they be accurately modeled. To investigate the impact of the inclusion of explicit treatment...
Article
Background: The bacterial cell envelope is comprised of the cell membrane and the cell wall. The bacterial cell wall provides rigidity to the cell and protects the organism from potential harmful substances also. Cell wall biosynthesis is an important physiological process for bacterial survival and thus has been a primary target for the developme...
Article
RNA molecules perform a variety of biological functions for which the correct three-dimensional structure is essential, including as ribozymes where they catalyze chemical reactions. Metal ions, especially Mg2+, neutralize these negatively charged nucleic acids and specifically stabilize RNA tertiary structures as well as impact the folding landsca...
Article
Full-text available
Sodium laureth sulfate (SLES) and fatty acids are common ingredients in many cosmetic products. Understanding how neutral and charged fatty acid compounds partition between micellar and water phases is crucial to achieve the optimal design of the product formulation. In this paper, we first study the formation of mixed SLES and fatty acids micelles...
Article
Background: Fragment-based ligand design is used for the development of novel ligands that target macromolecules, most notably proteins. Central to its success is the identification of fragment binding sites that are spatially adjacent such that fragments occupying those sites may be linked to create drug-like ligands. Current experimental and com...
Article
Full-text available
Targeting Clostridium difficile infection is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent C. difficile strains often have a binary toxin termed the C. difficile toxin, in addition to the enterotoxins TsdA and TsdB. The C. difficile toxin has an enzymatic component...
Article
Accurate force-field (FF) parameters are key to reliable prediction of properties obtained from molecular modeling (MM) and molecular dynamics (MD) simulations. With ever-widening applicability of MD simulations, robust parameters need to be generated for a wider range of chemical species. The CHARMM General Force Field program (CGenFF, https://cge...
Preprint
Full-text available
Targeting Clostridium difficile infection (CDI) is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent CDI often has a binary toxin termed the C. difficile toxin (CDT), in addition to the enterotoxins TsdA and TsdB. CDT has an enzymatic component, termed CDTa, and a pore...
Article
Filizola and co-workers have applied a combination of long-time molecular dynamics and oscillating chemical potential grand canonical Monte Carlo/molecular dynamics to investigate the distribution of Mg2+ and Na+ in the μ-opioid receptor and their impact on its function. Results indicate atomic details of potential mechanisms by which Mg2+ leads to...
Article
Cation-π interactions are noncovalent interactions between a π-electron system and a positively charged ion that are regarded as a strong noncovalent interaction and are ubiquitous in biological systems. Similarly, though less studied, anion-ring interactions are present in proteins along with in-plane interactions of anions with aromatic rings. As...
Preprint
Full-text available
RNA molecules perform a variety of biological functions for which the correct three-dimensional structure is essential, including as ribozymes where they catalyze chemical reactions. Metal ions, especially Mg ²⁺ , neutralize these negatively charged nucleic acids and specifically stabilize RNA tertiary structures as well as impact the folding lands...
Article
Full-text available
In this work, we report the development of Drude polarizable force-field parameters for the carboxylate and N-acetyl amine derivatives, extending the functionality of existing Drude polarizable carbohydrate force field. The force field parameters have been developed in a hierarchical manner, reproducing the quantum mechanical (QM) gas-phase propert...
Article
Full-text available
Significance KRas is the most frequently mutated oncogene in human cancer, and its critical role in tumorigenesis is well established. Historical challenges in targeting KRas have led to its characterization as an “undruggable” target, but recent advances in drug discovery approaches have revealed promising avenues toward the development of small m...
Chapter
Full-text available
Molecular dynamics (MD) simulations have been widely applied to computer-aided drug design (CADD). While MD has been used in a variety of applications such as free energy perturbation and long-time simulations, the accuracy of the results from those methods depends strongly on the force field used. Force fields for small molecules are crucial, as t...
Article
Full-text available
The inclusion of explicit polarization in molecular dynamics simulation has gained increasing interest during the last several years. An understudied area is the role of polarizability in computer simulations of solvation dynamics around chromophores, particularly for the large solutes used in experimental studies. In this work, we present fully po...
Article
Full-text available
Many applications in chemistry, biology, and energy storage/conversion research rely on molecular simulations to provide fundamental insight into structural and transport properties of materials with high ionic concentrations. Whether the system is comprised entirely of ions, like ionic liquids, or is a mixture of a polar solvent with a salt, e.g.,...
Article
Chemical fragment cosolvent sampling techniques have become a versatile tool in ligand-protein binding prediction. Site-Identification by Ligand Competitive Saturation (SILCS) is one such method that maps the distribution of chemical fragments on a protein as free energy fields called FragMaps. Ligands are then simulated via Monte Carlo techniques...
Poster
Full-text available
Impact of branching on the conformational heterogeneity of the lipopolysaccharide from Klebsiella pneumoniae: Implications for vaccine design