A Free Energy Based Computational Pathway from Chemical Templates to Lead Compounds: A Case Study of COX-2 Inhibitors

Latha, N.; Jain, Tarun; Sharma, Pankaj; Jayaram, B.

doi:10.1080/07391102.2004.10506969

Cited by 8 publications

(9 citation statements)

References 60 publications

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“…Preliminary studies conducted on several small molecules comprising some known NSAIDs and non-NSAIDs for COX-2 target demonstrated that the protocol could segregate drugs from non-drugs [230]. Jorgensen and coworkers investigated the binding of celecoxib and analogs to COX-2 via free energy perturbation method [231] as well as extended linear response formulation of the free energy based on Monte Carlo simulations [232].…”

Section: Cox-2mentioning

confidence: 99%

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

Latha¹,

Jayaram

2005

DDRO

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Drug discovery in the 21 st century is expected to be different in at least two distinct ways: development of individualized medicine utilizing genomic information and emergence of an integrated in silico protocol for facilitating target identification, structure prediction and lead discovery. The expectations from computational methods for developing suggestions on potential leads reliably and expeditiously, are continuously on the increase. Several conceptual and methodological concerns remain before an automation of lead design in silico could be contemplated. The novelty of the candidates generated, their geometries, the partial atomic charges and other force field parameters for enabling energy evaluations is one concern. A proper account of the flexibility of the candidate molecule and the target, a consideration of solvent and salt effects in binding and a reliable methodology for developing quantitative estimates of binding affinities is another. Finally the drug-likeness of the candidates generated is yet another concern. Each of these issues warrants a careful consideration. In this review, we sketch a system independent, binding free energy based, comprehensive computational pathway from chemical templates to lead-like molecules, given the three dimensional structure of the target protein and a definition of its active site, focusing on some emerging in silico trends and techniques. We survey current methods for generation of candidate molecules and some popular protocols for docking candidates in the protein active site. We discuss the theory of protein-ligand binding in the rigorous framework of statistical mechanics and assess the current strategies for affinity based filtering of candidates. We address concerns related to flexibility of the target and the candidate, solvent and salt effects in lead design. We present a realization of the pathway proposed in a high performance computing environment for cyclooxygenase-2 target wherein the computational protocols could sort drugs from nondrugs, assuring the viability of the overall strategy. We highlight a few case studies indicating the current level of agreement between theory and experiment in eliciting binding affinities. Finally, we present a critical assessment of the computational steps involved in binding affinity based active site directed lead molecule design and further improvements envisioned for potential automation.

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Section: Cox-2mentioning

confidence: 99%

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

Latha¹,

Jayaram

2005

DDRO

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“…The process of structure-based drug design is an iterative one and often proceeds through multiple cycles before an optimized lead goes into clinical trials [13,14]. High throughput screening is the physical screening of large libraries of chemical compounds against a biological target and is still the dominant technique in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

From Drug Target to Leads-Sketching A Physicochemical Pathway for Lead Molecule Design In Silico

Shaikh¹,

Jain²,

Sandhu³

et al. 2007

CPD

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The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss the significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.

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“…Active-Site Directed Drug Lead Molecule Design Software Suite (http://www.scfbioiitd.res.in/research/drugdesign.htm ) A comprehensive software suite, Sanjeevini [7,8] has been developed for target directed drug design. The software is system-independent and accomplishes lead-like molecule design based on binding affinities (the standard free energies of binding between target macromolecule and the candidate drug).…”

Section: Sanjeevinimentioning

confidence: 99%

From Gene to Drug: A Proof of Concept for a Plausible Computational Pathway

Shenoy

Jayaram

Latha

et al. 2006

Sixth International Conference on Intelligent Systems Design and Applications

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A Free Energy Based Computational Pathway from Chemical Templates to Lead Compounds: A Case Study of COX-2 Inhibitors

Cited by 8 publications

References 60 publications

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

From Drug Target to Leads-Sketching A Physicochemical Pathway for Lead Molecule Design In Silico

From Gene to Drug: A Proof of Concept for a Plausible Computational Pathway

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