#Pharmacophore

Pharmacophore Modeling in Drug Discovery Design, Ligand Based Drug Design, Fundamentals of Docking, SAR,QSAR Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs. In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process. Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge. However, the pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design.
Keywords: ADME-tox, computer-aided drug design, pharmacophore fingerprint, protein design, virtual screening
What is computer-aided drug design?
Drug design is an expensive and laborious process of developing new medicine. This process has its origin in herbal remedies dating back millennia.1 Only since the last century have drugs had a (semi)synthetic origin.2 The first hit compounds often lack both potency and safety, and must therefore be optimized. While historically this was a trial-and-error process,3,4 soon rational strategies were developed to improve potency.5,6 As with any data handling procedures, computers have become a more prominent and ubiquitous tool in drug discovery since the 1980s.7 The crossover between computational and pharmaceutical research is typically designated computer-aided drug design (CADD).8,9
CADD covers a broad range of applications spanning the drug discovery pipeline, although these are highly clustered in the early phases. The main purpose of CADD is to speed up and rationalize the drug design process while reducing costs.10 The aim of the earliest phase in drug discovery is to identify the first hit compounds, which is sometimes attempted by high-throughput screening (HTS), the testing of many thousands of compounds with a suitable activity assay. The in silico counterpart of in vitro HTS is referred to as virtual screening and aims at filtering libraries of molecules using computational methods to prioritize those most likely to be active for a given target.11 Later in the drug discovery pipeline the potency of the hit and lead compounds needs to be improved.12 New derivatives are designed with or without a different scaffold at the core of the molecule.13 The ultimate goal is to design highly potent and specific molecules which also have a suitable intellectual property position.14 This can be achieved by classical medicinal chemistry approaches, where the design can be based on the observed structure-activity relationships (SAR) or based on structural information.15 Computational methods however can also be used to create diverse derivatives based on different scaffolds,16,17 and then score them for improved potency. This prioritizes the most promising derivatives from a very wide chemical space in a relatively short time.18,19 However, the potency of the compounds is not the only consideration. Pharmacokinetic properties (absorption, distribution, metabolism, excretion) and toxicity, referred to as ADME-tox, are also of vital importance if a compound is to be clinically useful.20-22 As well as a battery of in vitro and in vivo experiments, virtual methods have also been developed to predict the ADME-tox profile of drug-like compounds early during the development process.
The basis of all CADD methods is chemo-informatics, the application of data storage, handling, and retrieval methods to chemical structures, their properties, and biological activity.23,24 Chemo-informatics also covers the calculation of molecular descriptors that describe a chemical or physical property based on the molecules’ structure, and which can be used for filtering compounds.25 In order to be able to compare and quantify (dis)similarity between molecules, molecular fingerprints are often the methods of choice.26
Another very important CADD subfield focuses on quantitative structure activity/property relationship (QSAR/QSPR), in which the physicochemical properties (as calculated by molecular descriptors) of a set of inhibitors are related to the inhibitory activity or toxicity to construct a predictive model for novel inhibitors.27-29 QSAR has become a very popular tool to profile novel inhibitors accurately in silico without going through expensive and time-consuming in vitro and in vivo assays.

[@HinduWarrior691]

Very good video, I learn several Softwares from a single video. More useful to researchers in the drug discovery field, Thank u.

[@aalilouyoussra3365]

a lot of love for ndian people with their generosity

[@premkumarb7862]

Thank you Sir. Very useful and simple step by step explanation, useful to many researchers

[@Dockingbydushyanthreddy]

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[@rahimeeshaghimalekshah3471]

your teaching is very simple and great, I definitely learn it, thank you, Dr Malekshah from Iran

[@Dockingbydushyanthreddy]

Great welcome please subscribe and share my lectures with your friends and others feel free to contact me on WhatsApp or email [e-mail]

[@rahimeeshaghimalekshah3471]

@@Dockingbydushyanthreddy I want to learn Qsar, how do I learn it?

[@Dockingbydushyanthreddy]

I will teach you

[@Dockingbydushyanthreddy]

Contact me on Watsapp 8919754133

[@rahimeeshaghimalekshah3471]

@@Dockingbydushyanthreddy thank you? how? in this youtub?

[@arkamondal8872]

Thank you sir for your videos.it is really very helpful for any beginners. Waiting for your more videos. Please add more videos on autodock

[@Dockingbydushyanthreddy]

Please subscribe and share my lectures please specify which topic you are interested

[@madhavimadhavaram1686]

Super sir really nice

[@Dockingbydushyanthreddy]

Keep watching enjoy and share my lectures

[@rashmimahabal212]

Sir can we add our own designed molecules for pharmacophore mapping

[@padmak1657]

Thankyou 👍

[@Dockingbydushyanthreddy]

Welcome to my channel Please Subscribe and share my lectures as much as you can feel free to contact me on watsapp @8919754133

[@Matladi474]

Thank you very much for this well articulated video. I am new to Pharmacophore Modeling and I have perfomed docking on a protein and ligand (drug), so my question is how do I know which pharmacophores are responsible for the interactions between the two?. Can I assume that the descriptors I am getting after loading the two before "submit query" is what is responsible for the interactions?. If so how do I download the table of this descriptors ? and picture of my protein-ligand complex?.

[@Dockingbydushyanthreddy]

Dear viewer; please note that thorough literature to be done and find the pharmacophore and its descriptors and u may design similar descriptors and try to impose on the exiting pharmacophore this technique is called as DYLLOMS

[@uzairmarwat4539]

Your videos are really very helpful. could you please make a video about Pharmacophore modeling via MOE?

[@Dockingbydushyanthreddy]

I am not familiar with moe

[@ManhaClub]

Sir gene related disease ka receptor kese find kre ge for drug design plz guide me

[@bmnangat]

I have an out of context question, can you demonstrate Lumo properties of a methyl side chain against an amine side chain let say in the activity of a propionic acid group which is responsible for antiinflammatory activity.

[@Dockingbydushyanthreddy]

dear student; homo lumo and discrete docking studies require DFT perturbations and simultaneous docking which is not performed here

[@abhikkumarray91]

Very nice lots of things clear. Sir! I want to read some articles. please send me some articles. How could I contact with you?

[@Dockingbydushyanthreddy]

Subscribe to my channel and share my lectures as much as you can ....you can contact me on watsapp 8919754133 and gmail [e-mail]

[@mahmoudmustafa2805]

Hi Dr Dushyanth It's pleasure to write you. actualy i have a problem with Zincpharmer. could you help me to solve this problem. Error connecting to search engine. Please try again later and if the problem persists, contact the administrator. keep in contact. best regards Mahmoud

[@Dockingbydushyanthreddy]

its is evident that u might be performing some errors kindly follow steps provided

[@shakibavahdat9869]

Thank you so much for your video, I would what to know after I got my hits , how do I decide which one to choose for further study? Based on SAR ? or best overlay? Thanks

[@Dockingbydushyanthreddy]

score of resemblence

[@shilpivats3207]

Sir, can you make video on pharmacophore modelling manually as it is available in Free Discovery studio visualizer?

[@Dockingbydushyanthreddy]

Please subscribe and share my lectures with your friends and others feel free to call me on WhatsApp [phone] surely I will make video new lectures will add up in next week thank you

[@shilpivats3207]

@@Dockingbydushyanthreddy thanks sir

[@elainejoytorre2191]

May I ask why it is called Ligand-based modelling if the protein is added on ZincPharmer? I'm confused, can you help me? Thank youp

[@Dockingbydushyanthreddy]

It’s not a ligand based mondeling ....it can be called only once an ensemble of ligands are used to generate a common pharmacophore...here it is interactive ligand receptor based pharmacophore ...here pharmacophore is specific. To active site ...it is mostly can be termed as receptor based or interactive ligand based ...don’t confuse yourself ....please subscribe and share with your friends and others feel free to call me on WhatsApp or email at 8919754133 [e-mail]

[@VikasKumar-bn6rf]

From whre we can add filters while selecting ligands for Lipinski rule and all after getting hits after zinc software

[@Dockingbydushyanthreddy]

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[@jagdishchand9321]

Sir the hit molecules after submit query...how to do docking for best hits compunds other than the CLC GENOMIC WORKBENCH.. as this software is paid. Please can you tell some other softwares that are free. Thank you.

[@Dockingbydushyanthreddy]

autodock

[@shyamdholakia4270]

How you did the virtual screening? Software?

[@Dockingbydushyanthreddy]

Contact me on Watsapp 8919754133 and subscribe and share my lectures....

[@yusufganteng78]

Hello sir

[@anweshadas6077]

Respected sir... Can we do pharmacophore modelling using only the ligand molecule?

[@Dockingbydushyanthreddy]

yes u can

[@anweshadas6077]

@@Dockingbydushyanthreddy thank you sir

[@zahidnaseem4572]

Very useful video, Thanks. Could you please upload a tutorial for the docking of Zn database using MOE?

[@Dockingbydushyanthreddy]

Please subscribe and share my lectures with your friends and others feel free to call me on my Watsaap 8919754133 or by email [e-mail]

[@Dockingbydushyanthreddy]

Moe and zinc are two different things can’t be clubbed

[@zahidnaseem4572]

First of all thanks for your response. Secondly, I mentioned Zn database not Zn. Zn database is actually a database containing a large no of chemical structures, can be docked against different proteins to have potential hits.

[@Dockingbydushyanthreddy]

My lectures is on zinc database obviously it will explain about database regarding moe multiple pharmacophores can’t be loaded into zinc database for virtual screening

[@zahidnaseem4572]

You mean we can't dock the zinc database using MOE, if I am not wrong.

[@manjiris.shinde4302]

Sir, from where did you removed heteroatoms? I'm not finding my notepad file

[@Dockingbydushyanthreddy]

Welcome to my channel please subscribe and share my lectures and contact me on Watsapp 8919754133

[@esraaabdelmoniem9874]

Hello sir, Every time I tried to submit a query in the zincpharmer gives me a server error. Could you tell me what is the problem

[@Dockingbydushyanthreddy]

Welcome to my channel subscribe to my channel and share my lectures contact me on email or Watsapp 8919754133 [e-mail]

[@esraaabdelmoniem9874]

I tried the whatsapp no. but I think something wrong with no. Could you tell me what is the key no of your country

[@Dockingbydushyanthreddy]

Esraa Abdelmoniem [phone]

[@stanzinstan6669]

Hlo sir...... Can u help me do pharmachophore model for metallobetalactamase enzyme

[@Dockingbydushyanthreddy]

Subscribe to my channel and share among your friends contact me on Watsapp tomorrow 8919754133

[@pharma-infowithsubhasis2752]

Sir,while loading features,everytime it appears server error processing ligand.how can it be solved?

[@Dockingbydushyanthreddy]

Can’t understand your question contact me on Watsapp 8919754133 during office hours

[@pharma-infowithsubhasis2752]

@@Dockingbydushyanthreddy thank you Sir.

[@Dockingbydushyanthreddy]

Subscribe and share my lectures

[@pharma-infowithsubhasis2752]

@@Dockingbydushyanthreddy sure Sir.gud nt.

[@way2pharma463]

sir, its showing 0 hits, then what to do

[@Dockingbydushyanthreddy]

Please subscribe and share my lectures you need to refine the search by editing the descriptors in the pharmacophore step by step by selecting various descriptors alternatively

[@madhavimadhavaram1686]

Sir is it possible to screen aquari results using MVD

[@Dockingbydushyanthreddy]

What do u mean by Aquari

[@madhavimadhavaram1686]

Sorry sir that is query

[@Dockingbydushyanthreddy]

Yaa u can do

[@madhavimadhavaram1686]

I got 37 thousand hits by screening pharmacophors, but I don't know weather my MVD screens this large number of compounds

[@Dockingbydushyanthreddy]

Yes u can dock even with lakhs ....