Computational structure‐based drug design: Predicting target flexibility

Iglesias, Jelisa; Saen‐oon, Suwipa; Soliva, Robert; Guallar, Vı́ctor

doi:10.1002/wcms.1367

Cited by 17 publications

(17 citation statements)

References 193 publications

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“…1PP9 ( Bos taurus ) having an experimental resolution of 2.1 Å was selected as the main template and used to guide the modeling process [ 49 ]. The precision of the modeled structure has been suggested to be more refined upon the use of several templates and this was utilized in this study to improve model quality and resolution of more mobile protein segments [ 51 , 52 ]. After modeling, the quality of the structures was further assessed using the in-built I-TASSER metrics, Ramachandran plot and z-DOPE score.…”

Section: Resultsmentioning

confidence: 99%

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

Chebon

Sanyanga

Manyumwa

et al. 2021

IJMS

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Atovaquone (ATQ) is a drug used to prevent and treat malaria that functions by targeting the Plasmodium falciparum cytochrome b (PfCytb) protein. PfCytb catalyzes the transmembrane electron transfer (ET) pathway which maintains the mitochondrial membrane potential. The ubiquinol substrate binding site of the protein has heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors that act as redox centers to aid in ET. Recent studies investigating ATQ resistance mechanisms have shown that point mutations of PfCytb confer resistance. Thus, understanding the resistance mechanisms at the molecular level via computational approaches incorporating phospholipid bilayer would help in the design of new efficacious drugs that are also capable of bypassing parasite resistance. With this knowledge gap, this article seeks to explore the effect of three drug resistant mutations Y268C, Y268N and Y268S on the PfCytb structure and function in the presence and absence of ATQ. To draw reliable conclusions, 350 ns all-atom membrane (POPC:POPE phospholipid bilayer) molecular dynamics (MD) simulations with derived metal parameters for the holo and ATQ-bound -proteins were performed. Thereafter, simulation outputs were analyzed using dynamic residue network (DRN) analysis. Across the triplicate MD runs, hydrophobic interactions, reported to be crucial in protein function were assessed. In both, the presence and absence of ATQ and a loss of key active site residue interactions were observed as a result of mutations. These active site residues included: Met 133, Trp136, Val140, Thr142, Ile258, Val259, Pro260 and Phe264. These changes to residue interactions are likely to destabilize the overall intra-protein residue communication network where the proteins’ function could be implicated. Protein dynamics of the ATQ-bound mutant complexes showed that they assumed a different pose to the wild-type, resulting in diminished residue interactions in the mutant proteins. In summary, this study presents insights on the possible effect of the mutations on ATQ drug activity causing resistance and describes accurate MD simulations in the presence of the lipid bilayer prior to conducting inhibitory drug discovery for the PfCytb-iron sulphur protein (Cytb-ISP) complex.

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Section: Resultsmentioning

confidence: 99%

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

Chebon

Sanyanga

Manyumwa

et al. 2021

IJMS

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“…Rigid docking only provides rough estimation about the thermodynamics of binding, enables high throughput performance. 51…”

Section: P-103mentioning

confidence: 99%

A Review on Recent Rational Approaches to Drug Design, Development and Its Discovery

Dheeraj¹,

Rajeshwar²,

Govind³

et al. 2022

Int J Life Sci Pharm Res

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The steps involved in drug design, drug development and drug discovery are highly expensive, extremely challenging and time consuming. Although the drug designing, process has been hastened with the development of newer emerging techniques, and the fabrication of novel computational tool. Researchers are working on structure guided drug designing using a 3-D structure of target, the drug molecule identified by the use of target-based drug design shows great potential in preventing various diseases but also possess many side effects. In the rational drug design, structure-based designing, combinatorial drug designing and computer aided drug design techniques are employed. When gene expression and bioinformatics are incorporated with the combinatorial drug designing, that make the rational drug designing, a more powerful tool for drug discovery. The rational drug designing associated with gene expression and bioinformatical estimation is moderately emerging and expeditiously revamping the drug development with less time consuming, economic, effectiveness and cater novel combinatory therapy in addition to minimization of toxicity. This review discusses in detail about the fabrication of a successful drug candidate using multidisciplinary perspective of combinatorial chemistry with gene expression analysis, structure based and artificial intelligencebased drug designing. In future, more sophisticated computer-based methodologies would be required for developing new drug candidate.

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“…The Glide, 135 LigandFit, 136 and FlexX 103 codes use Grid computing 137 (Section 2.2) to distribute docking jobs to multiple computers over a network. This shortens the time to solution of large‐scale molecular docking that allows for introducing receptor flexibility 6,119 and improves the accuracy of the scoring function.…”

Section: Hpc: Applicationsmentioning

confidence: 99%

“…Developing a new drug molecule can cost up to $2.6 billion: the use of computational approaches may decrease such costs by 30%, as well as the research time by several months 3 . The computational investigations of target/ligand complexes may help discover drug leads, compounds with at least micromolar affinity for their targets 4–7 . In particular, computational structure‐based drug design (CSBDD) has played a significant role in discovering many FDA‐approved drugs that reached the consumer market 8–11 …”

Section: Introductionmentioning

confidence: 99%

Expanding the boundaries of ligand–target modeling by exascale calculations

Bolnykh

Rossetti

Rothlisberger

et al. 2021

WIREs Comput Mol Sci

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Molecular simulations and molecular docking are widely used tools to investigate ligand/target interactions and in drug design. High‐performance computing (HPC) is boosting both the accuracy and predictive power of these approaches. With the advent of exascale computing, HPC may become standardly applied in many drug design campaigns and pharmacological applications. This review discusses how innovative HPC algorithms and hardware are being exploited in current simulations and docking codes, pointing also at some of the limitations of these approaches. The focus is on technical aspects which might not be all that familiar to the computational pharmacologist. This article is categorized under: Software > Molecular Modeling Software > Simulation Methods Structure and Mechanism > Computational Biochemistry and Biophysics

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Computational structure‐based drug design: Predicting target flexibility

Cited by 17 publications

References 193 publications

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

A Review on Recent Rational Approaches to Drug Design, Development and Its Discovery

Expanding the boundaries of ligand–target modeling by exascale calculations

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